Quisinostat (DB12985): A Comprehensive Review of Its Preclinical and Clinical Development as an HDAC Inhibitor in Oncology

1. Executive Summary

Quisinostat (DrugBank ID: DB12985; CAS Number: 875320-29-9), also known by its development code JNJ-26481585, is an orally bioavailable, second-generation hydroxamic acid-based histone deacetylase (HDAC) inhibitor. It exhibits potent, sub-nanomolar inhibitory activity against Class I HDACs, particularly HDAC1, and modest activity against certain Class II HDACs. Its mechanism of action involves the induction of histone hyperacetylation, leading to chromatin remodeling, altered gene expression, and ultimately, anti-tumor effects such as apoptosis, cell cycle arrest, and inhibition of tumor cell proliferation. Quisinostat also influences the acetylation status of non-histone proteins, contributing to its complex biological activity.

Developed initially by Janssen Pharmaceuticals and later co-developed in specific regions by NewVac LLC, Quisinostat has undergone extensive preclinical evaluation demonstrating broad in vitro cytotoxicity against various cancer cell lines and in vivo efficacy in several xenograft models, including notable activity as a brain-penetrant radiosensitizer in glioblastoma models.

Clinically, Quisinostat has been investigated in Phase I and Phase II trials across a spectrum of hematological malignancies (Cutaneous T-Cell Lymphoma, Leukemia, Myelodysplastic Syndromes, Multiple Myeloma) and solid tumors (Ovarian Cancer, Glioblastoma, Non-Small Cell Lung Cancer, and others). Efficacy signals have been mixed: promising activity was observed in combination with chemotherapy for platinum-resistant ovarian cancer (Objective Response Rate of 50%), and modest activity in relapsed/refractory Cutaneous T-Cell Lymphoma (24% cutaneous response rate). However, development has been discontinued for several indications, including CTCL, leukemia, MDS, and multiple myeloma, potentially due to insufficient efficacy or challenging safety profiles. A significant safety concern is cardiovascular toxicity, including QT prolongation and arrhythmias, which have been dose-limiting. Intermittent dosing schedules have been explored to mitigate toxicity.

Pharmacokinetic studies indicate dose-proportional exposure, with a relatively short plasma half-life (2-4 hours for the oral formulation). The drug is an inhibitor of CYP2D6 and P-glycoprotein, indicating a potential for drug-drug interactions. Currently, Quisinostat remains an investigational agent, with ongoing or planned development focused on areas where its specific properties, such as brain penetration and radiosensitization, may offer a therapeutic advantage, exemplified by a planned Phase 0/Ib trial in glioblastoma.

2. Introduction to Quisinostat (DB12985)

Overview and Therapeutic Rationale

Quisinostat, identified by DrugBank accession number DB12985 and CAS number 875320-29-9, also widely known by its development code JNJ-26481585, is an investigational small molecule drug.[1] It has been the subject of numerous clinical trials for a variety of oncological conditions. Initial investigations and background information highlight its exploration in the treatment of Lymphoma, various Neoplasms, Myelodysplastic Syndromes (MDS), and Advanced or Refractory Leukemia.[1]

The fundamental therapeutic rationale underpinning the development of Quisinostat is its function as a histone deacetylase (HDAC) inhibitor.[5] HDACs are a class of enzymes that play a pivotal role in epigenetic regulation. They catalyze the removal of acetyl groups from lysine residues on both histone and non-histone proteins. This deacetylation process generally leads to a more condensed chromatin structure, which can restrict the access of transcriptional machinery to DNA, thereby repressing gene expression.[5] In many types of cancer, the activity of HDACs is dysregulated, contributing to aberrant gene expression patterns that promote tumor initiation, progression, and resistance to therapy. By inhibiting HDACs, Quisinostat aims to reverse these epigenetic alterations, leading to an accumulation of acetylated histones. This, in turn, can induce chromatin relaxation, reactivate silenced tumor suppressor genes, and trigger various anti-tumor cellular responses, including programmed cell death (apoptosis), cell cycle arrest, and inhibition of tumor cell proliferation and division.[1]

Development History and Key Developers

Quisinostat was originally developed by Janssen Pharmaceuticals, a pharmaceutical company of Johnson & Johnson.[19] Subsequently, NewVac LLC, a subsidiary of the ChemRar High Tech Center and a resident of the Skolkovo Innovation Center in Russia, entered into a co-licensing agreement with Janssen Pharmaceutica NV for Quisinostat.[20] This agreement granted NewVac exclusive rights for the development and commercialization of the compound in Russia and several other Eastern European countries. Under this arrangement, NewVac was responsible for conducting research and development, including supporting clinical trials within these territories, while Janssen was to contribute its expertise in global clinical trial management.[22]

This dual-developer model, where a major pharmaceutical company partners with a regional entity, is a common strategic approach in the pharmaceutical industry. It allows for the leveraging of regional expertise, potentially optimizing clinical trial recruitment, navigating local regulatory landscapes more effectively, and managing development costs. For a compound like an HDAC inhibitor with potential applications across multiple cancer types, such partnerships can help maximize its global development reach and market potential while distributing the inherent risks and substantial financial investment associated with oncology drug development. The involvement of the Skolkovo Innovation Center further suggests a focus on fostering research and development capabilities within Russia for NewVac's activities.[22]

3. Physicochemical Properties and Formulation

Chemical Identification

Quisinostat is recognized by its International Nonproprietary Name (INN) and US Adopted Name (USAN) as Quisinostat.[1] Its unique Chemical Abstracts Service (CAS) Registry Number is 875320-29-9.[1] In drug databases, it is cataloged under DrugBank ID DB12985.[1] The most frequently cited development code name for Quisinostat is JNJ-26481585, often used in preclinical and early clinical study reports.[1] Other database identifiers include UNII: 9BJ85K1J8S, ChEBI: CHEBI:94771, and ChEMBL: CHEMBL2105763.[1]

Molecular Structure, Formula, and Weight

Quisinostat is classified chemically as a hydroxamic acid-based compound. Its structure incorporates a methylindole moiety, a piperidine ring, and a pyrimidine ring.1

The molecular formula for Quisinostat is C21H26N6O2.1 Its molecular weight is consistently reported as approximately 394.47 g/mol or 394.5 g/mol.1 The International Union of Pure and Applied Chemistry (IUPAC) name for Quisinostat is N-hydroxy-2-(4-((((1-methyl-1H-indol-3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxamide.1

Solubility, Stability, and Known Formulations

Quisinostat typically presents as a solid powder.[12] It is soluble in dimethyl sulfoxide (DMSO), a common solvent for in vitro studies.[25] For in vivo animal studies, various formulations have been utilized to achieve adequate solubility and administration, including combinations of 10% DMSO with co-solvents such as polyethylene glycol 300 (PEG300), Tween-80, saline, sulfobutylether-beta-cyclodextrin (SBE-β-CD), or corn oil, generally achieving a solubility of ≥ 2.5 mg/mL.[26] For storage, it is recommended to keep the powdered form at -20°C and solutions in solvent at -80°C to maintain stability.[25]

In clinical settings, Quisinostat has been primarily administered orally, typically in capsule form, with dosages such as 12 mg being used in various trial protocols.[23] The oral bioavailability of Quisinostat is a key characteristic, facilitating its administration, particularly for potentially chronic or long-term treatment regimens in cancer patients.[1]

Beyond conventional oral formulations, advanced drug delivery systems have been explored preclinically. Notably, an injectable hydrogel formulation incorporating Quisinostat along with gold nanoparticles (AuNP) as a contrast agent has been investigated.[35] This system was designed for localized delivery, particularly for glioblastoma (GBM), with the innovative feature of radiation-triggered drug release. Such targeted delivery strategies aim to enhance local drug concentrations at the tumor site while minimizing systemic exposure, thereby potentially improving the therapeutic index by increasing efficacy and reducing side effects. This approach is particularly relevant for treating challenging tumors like GBM, where the blood-brain barrier and systemic toxicities of potent agents like HDAC inhibitors pose significant challenges.

Table 1: Key Physicochemical Properties of Quisinostat

Property	Value	Reference(s)
Official Name	Quisinostat	1
Common Synonyms	JNJ-26481585	1
CAS Number	875320-29-9	1
DrugBank ID	DB12985	1
Molecular Formula	C21H26N6O2	1
Molecular Weight	~394.47 g/mol	1
Chemical Class	Hydroxamic acid, methylindole, piperidine, pyrimidine	1
Appearance	Solid powder	12
Key Solubility	Soluble in DMSO; various co-solvent formulations for in vivo use (≥ 2.5 mg/mL)	25
Storage Conditions	Powder: -20°C; In solvent: -80°C	25

4. Mechanism of Action and Pharmacodynamics

Role as a Histone Deacetylase (HDAC) Inhibitor

Quisinostat is a second-generation, orally bioavailable, hydroxamic acid-based compound that functions as a potent inhibitor of histone deacetylases (HDACs).[1] While often described as a "pan-HDAC inhibitor" due to its activity against multiple HDAC isoforms, it exhibits a distinct selectivity profile within the HDAC family.[11] HDACs are critical epigenetic modulators that remove acetyl groups from lysine residues on histones and various non-histone proteins. This deacetylation typically leads to a more compact chromatin structure, limiting the accessibility of DNA to transcription factors and thereby repressing gene expression.[6] In numerous cancers, HDAC activity is dysregulated, contributing to an oncogenic transcriptional program.

Selectivity Profile for HDAC Isoforms

Quisinostat demonstrates high potency against Class I HDACs (HDAC1, HDAC2, HDAC3) and certain Class IIb HDACs (HDAC10, HDAC11).7 Its selectivity profile, based on reported IC50 values (the concentration required for 50% inhibition), is detailed in Table 2.

Notably, Quisinostat exhibits its highest potency against HDAC1, with a reported IC50 of 0.11 nM in cell-free assays.11 This is particularly significant as HDAC1 has been identified as an essential enzyme for the survival of glioma stem cells (GSCs) in glioblastoma (GBM) and its expression correlates with poorer prognosis in this malignancy.6 The potent inhibition of HDAC1 likely underpins much of Quisinostat's observed anti-tumor activity, especially in cancers like GBM.

The drug also potently inhibits HDAC2 (IC50: 0.33 nM), HDAC10 (IC50: 0.46 nM), and HDAC11 (IC50: 0.37 nM), and shows modest potency for HDAC4 (IC50: 0.64 nM).11 It demonstrates over 30-fold selectivity against HDACs 3, 5, 8, and 9, and has the lowest reported potency for HDAC6 and HDAC7.11 Despite a lower potency for HDAC6, target engagement, as indicated by increased acetylation of tubulin (an HDAC6 substrate), has been observed in tumor biopsies from patients with Cutaneous T-Cell Lymphoma (CTCL) treated with Quisinostat.29 This suggests that even at clinically relevant doses, some inhibition of HDAC6 activity may occur. The broader activity spectrum against multiple HDAC isoforms contributes to its classification as a pan-HDAC inhibitor, but this broad activity may also contribute to its toxicity profile.

Table 2: HDAC Isoform Selectivity and Potency of Quisinostat

HDAC Isoform	IC50 (nM)	Potency Description	Reference(s)
HDAC1	0.11	Highest	11
HDAC2	0.33	High	11
HDAC11	0.37	High	11
HDAC10	0.46	High	11
HDAC4	0.64	Modest	11
HDAC3	>3.3 (approx. >30x less potent than HDAC1)	Low	11
HDAC5	>3.3 (approx. >30x less potent than HDAC1)	Low	11
HDAC8	>3.3 (approx. >30x less potent than HDAC1)	Low	11
HDAC9	>3.3 (approx. >30x less potent than HDAC1)	Low	11
HDAC6	Lowest reported potency	Low	11
HDAC7	Lowest reported potency	Low	11

Note: Potency descriptions are relative based on the provided data. IC50 values for HDACs 3, 5, 8, 9, 6, and 7 are not explicitly given as numerical values in all cited sources but are described in terms of selectivity relative to HDAC1.

Molecular Effects

The inhibition of HDAC enzymes by Quisinostat leads to several key molecular changes:

Histone Hyperacetylation: The primary molecular consequence is the accumulation of acetyl groups on lysine residues of histone proteins (e.g., H3K9/14ac, H3K27ac). This increased acetylation neutralizes the positive charge of histones, leading to a more relaxed, open chromatin structure (euchromatin), which enhances the accessibility of DNA to transcription factors and can reactivate the expression of previously silenced genes, including tumor suppressor genes.[1]
Impact on Non-Histone Proteins: HDACs also target a multitude of non-histone proteins involved in various cellular processes. Quisinostat-mediated HDAC inhibition can thus affect the acetylation status and function of these proteins. For example:
p53: Quisinostat treatment has been shown to upregulate p53 acetylation at specific lysine residues (K381/K382) by impairing the interaction between HDAC6 and p53, leading to p53 activation.[17]
HSP70 and Bcl-2: Compared to first-generation HDAC inhibitors, Quisinostat may induce superior upregulation of Heat Shock Protein 70 (HSP70) and downregulation of the anti-apoptotic protein Bcl-2.[11]
p21: It leads to the upregulation of p21 (CDKN1A), a cyclin-dependent kinase inhibitor involved in cell cycle control.[6]
Tubulin: Acetylation of α-tubulin, a substrate of HDAC6, has been observed in tumor biopsies following Quisinostat treatment, indicating target engagement of HDAC6 despite its lower in vitro potency.[29]
Other Proteins: Modulation of acetylation has also been reported for nucleolin, replication protein A 70 kDa DNA-binding subunit, phosphoglycerate kinase 1, stress-70 protein, the proto-oncogene Myc, and serine hydroxymethyltransferase.[7]

Cellular Consequences

The molecular effects of Quisinostat translate into several significant cellular consequences in cancer cells:

Apoptosis Induction: A hallmark of Quisinostat's anti-cancer activity is the induction of programmed cell death (apoptosis). This is often mediated through the activation of caspase cascades and modulation of apoptotic regulatory proteins like Bcl-2.[1]
Cell Cycle Arrest: Quisinostat can cause cancer cells to arrest at various phases of the cell cycle, commonly G1 or G2/S phase. This effect is often linked to the upregulation of cell cycle inhibitors like p21.[6]
DNA Damage and Repair Modulation: The drug has been shown to induce DNA damage, evidenced by increased levels of phosphorylated histone H2AX (γ-H2AX), a marker for DNA double-strand breaks. Furthermore, especially in combination with radiation, Quisinostat can downregulate DNA damage repair pathways, enhancing the cytotoxic effects of radiotherapy.[6]
Chromatin Remodeling and Gene Reactivation: By inducing histone hyperacetylation, Quisinostat facilitates chromatin remodeling to a more open state. This can lead to the re-expression of silenced tumor suppressor genes, contributing to its anti-neoplastic effects.[1]
Reversal of Epithelial to Mesenchymal Transition (EMT): Preclinical data indicate that Quisinostat can amplify the expression of HDAC-repressed E-cadherin, a key cell adhesion molecule. Increased E-cadherin expression is associated with the reversal of EMT, a process implicated in tumor invasion and metastasis.[2]

Target Engagement and Dose-Response Biomarkers

The pharmacodynamic effects of Quisinostat have been monitored in clinical trials using several biomarkers:

Histone Acetylation: Increased acetylation of histone H3 (specifically H3K9/14ac and H3K27ac) in readily accessible tissues such as hair follicles, skin biopsies, and peripheral blood mononuclear cells (PBMCs), as well as in tumor biopsies, has served as a key pharmacodynamic marker. This confirms systemic target engagement of HDAC enzymes by Quisinostat.[6]
Ki67 Reduction: A decrease in the proliferation marker Ki67 in skin and tumor biopsies has been observed, indicating an anti-proliferative effect consistent with the drug's mechanism.[28]
Acetylated Tubulin: In CTCL trials, an increase in acetylated tubulin in tumor biopsies was noted, suggesting engagement of HDAC6, even if its direct inhibition by Quisinostat is less potent compared to Class I HDACs.[29]

The consistent detection of histone hyperacetylation in various patient tissues at therapeutic doses provides strong evidence of systemic target engagement. This is crucial for validating the drug's mechanism of action in the clinical setting and for guiding dose selection and optimization in early-phase trials. The correlation of these molecular changes with markers of proliferation (Ki67) further strengthens the link between target modulation and desired anti-tumor outcomes.

5. Pharmacokinetics (PK)

Absorption and Bioavailability

Quisinostat is designed for oral administration and is reported to be orally bioavailable.[1]

Distribution

A significant characteristic of Quisinostat is its ability to penetrate the blood-brain barrier, which has been demonstrated in preclinical models. This property is particularly relevant for its potential application in treating central nervous system (CNS) malignancies such as glioblastoma (GBM).[6] Studies in orthotopic GBM models have shown that unbound levels of Quisinostat can be detected in normal brain tissue, and there is a higher accumulation in tumor tissue compared to the contralateral (non-tumor bearing) brain hemisphere.[6]

Metabolism and Excretion Pathways

Detailed information regarding the specific metabolic pathways of Quisinostat and its primary routes of excretion in humans is not extensively covered in the provided research snippets.[3] DrugBank also indicates that this information is "Not Available".[3] The absence of comprehensive metabolism and excretion data in the publicly accessible documents represents a knowledge gap. This information is vital for a complete understanding of the drug's disposition, potential for drug-drug interactions involving metabolic enzymes, variability in patient response due to genetic polymorphisms in metabolizing enzymes, and for appropriate dose adjustments in patients with impaired renal or hepatic function. Such details are typically found in comprehensive investigator brochures, full clinical study reports, or regulatory submission packages, which are beyond the scope of the provided materials.

Key Pharmacokinetic Parameters (from human studies)

Pharmacokinetic data from Phase I human studies have provided insights into Quisinostat's behavior in patients:

Dose Proportionality: The maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of Quisinostat have been shown to increase proportionally with the administered dose. This was observed for continuous daily dosing (2-12 mg) and intermittent dosing schedules (6-19 mg).[28] This dose proportionality is a favorable pharmacokinetic characteristic, as it suggests predictable and scalable exposure with dose adjustments, simplifying dose selection in clinical practice.
Steady-State Parameters for Oral Administration: Data from Inxight Drugs indicates the following steady-state parameters in Homo sapiens after once-daily oral administration [23]:
6 mg dose: Cmax ~0.828 ng/mL, AUC ~3.62 ng·h/mL, T1/2 ~2 hours.
8 mg dose: Cmax ~1.24 ng/mL, AUC ~9.77 ng·h/mL, T1/2 ~4.08 hours.
12 mg dose: Cmax ~2.155 ng/mL, AUC ~12.91 ng·h/mL, T1/2 ~2.76 hours.
Half-life (T1/2): Quisinostat is reported to have a prolonged period of half-elimination from tissues, which contributes to sustained inhibition of its target, HDAC1.[23] However, the plasma half-life values reported from steady-state oral dosing in humans are relatively short, ranging from approximately 2 to 4 hours depending on the dose.[23] This relatively short plasma half-life might necessitate frequent dosing or optimized intermittent schedules (such as the Monday, Wednesday, Friday regimen identified in Phase I studies) to maintain adequate target engagement and therapeutic concentrations over time. Nano-assembly formulations have been explored preclinically to extend the drug's half-life, with in vitro release times reported to vary from 5 to 14 days.[51]
Species-Specific Pharmacokinetic Differences: A critical finding from preclinical studies is the species-specific stability of Quisinostat. It is reported to be highly unstable in mouse plasma and brain tissue, likely due to degradation by carboxylesterases, which are highly active in rodents. In contrast, Quisinostat is significantly more stable in human plasma and brain tissue.[6] This difference is a crucial consideration for the translation of preclinical efficacy and toxicity data to human clinical trials, as drug exposure levels and duration can vary substantially between species. It underscores the importance of direct human pharmacokinetic and pharmacodynamic assessments to accurately predict clinical outcomes.

Table 3: Summary of Quisinostat Pharmacokinetic Parameters in Humans (Steady-State, Oral Administration)

Dose	Dosing Schedule	Cmax (ng/mL)	AUC (ng·h/mL)	T1/2 (hours)	Patient Population/Study Context	Reference(s)
6 mg	Once daily	0.828	3.62	2	Homo sapiens	23
8 mg	Once daily	1.24	9.77	4.08	Homo sapiens	23
12 mg	Once daily	2.155	12.91	2.76	Homo sapiens	23
2-12 mg	Continuous daily	Dose-proportional	Dose-proportional	Not specified for each dose	Advanced solid tumors	28
6-19 mg	Intermittent schedules	Dose-proportional	Dose-proportional	Not specified for each dose	Advanced solid tumors	28

6. Preclinical Evaluation

In Vitro Antitumor Activity

Quisinostat has demonstrated potent cytotoxic activity across a broad spectrum of human tumor cell lines in vitro. Studies have shown efficacy in cell lines derived from lung, breast, colon, prostate, brain, and ovarian cancers, with half-maximal inhibitory concentrations (IC50 values) typically ranging from 3.1 to 246 nM.[23] In testing against the Pediatric Preclinical Testing Program (PPTP) in vitro panel of cell lines, Quisinostat exhibited a median relative IC50 value of 2.2 nM, with a range of <1 nM to 19 nM, indicating high potency in pediatric cancer models as well.[8]

Specific preclinical efficacy has also been reported in melanoma cell lines [15] and in lung adenocarcinoma cells, where it was shown to disrupt epithelial barrier integrity.[47] Furthermore, Quisinostat effectively inhibits the growth of multiple patient-derived glioma stem cell (GSC) lines from GBM, a particularly aggressive brain tumor.[6]

In Vivo Efficacy in Animal Models

The in vitro activity of Quisinostat has translated to in vivo efficacy in various animal xenograft models of cancer.[6] For instance, daily intraperitoneal (IP) administration of Quisinostat at 10 mg/kg strongly inhibited the growth of established HCT116 colon cancer xenografts.[26]

In the PPTP in vivo panel, Quisinostat induced significant differences in event-free survival (EFS) distribution compared to control groups in 64% (21 out of 33) of evaluable solid tumor xenografts and in 50% (4 out of 8) of evaluable acute lymphoblastic leukemia (ALL) xenografts. Objective responses, including complete responses (CR) or maintained CRs, were observed in some T-cell ALL models and one solid tumor xenograft, with a third ALL xenograft achieving stable disease.[8] The most consistent in vivo activity signals in this pediatric panel were noted for glioblastoma and T-cell ALL xenografts.[8]

Beyond direct anti-tumor effects, Quisinostat has also demonstrated the ability to augment T-cell mediated anti-tumor responses. In an adoptive T-cell transfer model, treatment with Quisinostat led to increased proliferation of transferred T-cells and a skewing towards a CD8+ T-cell phenotype, suggesting an immunomodulatory role that could enhance cancer immunotherapy approaches.[18]

Studies on Radiosensitization (e.g., in Glioblastoma)

A significant area of preclinical investigation for Quisinostat has been its potential as a radiosensitizer, particularly for GBM. Multiple studies have confirmed that Quisinostat is a brain-penetrant molecule that can enhance the efficacy of radiation therapy in preclinical GBM models.6

The combination of Quisinostat with radiation has been shown to extend survival in orthotopic patient-derived xenograft (PDX) models of GBM.6 The underlying mechanism for this radiosensitization involves the induction of increased DNA damage (as measured by γ-H2AX foci) and the modulation of DNA damage repair pathways within the tumor cells.6

Further enhancing its potential for GBM treatment, an injectable hydrogel formulation of Quisinostat, designed for localized delivery and radiation-triggered release, has shown efficacy in GBM xenograft models.35

The potent radiosensitizing effect of Quisinostat, coupled with its ability to penetrate the brain, provides a strong scientific rationale for its clinical investigation in combination with radiotherapy for brain tumors like GBM. This is particularly relevant given the aggressive nature and poor prognosis associated with GBM, where novel therapeutic strategies are urgently needed. The planned Phase 0/Ib clinical trial (NCT06824662) for GBM [20] is a direct clinical translation of these promising preclinical findings, aiming to leverage Quisinostat's unique pharmacokinetic and pharmacodynamic properties in this challenging indication.

7. Clinical Development and Efficacy

Overview of Clinical Trial Program

Quisinostat has been evaluated in numerous Phase I and Phase II clinical trials across a diverse range of hematological malignancies and solid tumors.[2] The primary route of administration in these trials has been oral, often utilizing intermittent dosing schedules, such as three times per week, to manage tolerability.[3]

Hematological Malignancies

Lymphoma (Cutaneous T-Cell Lymphoma - CTCL / Mycosis Fungoides/Sézary Syndrome):
A key trial in this indication was NCT01486277, a Phase II multicenter study evaluating oral Quisinostat (8 mg or 12 mg, administered on days 1, 3, and 5 of each week in 21-day cycles) in patients with previously treated Stage IB-IVA Mycosis Fungoides (MF) or Sézary Syndrome (SS).[12]
Efficacy: The trial reported a cutaneous response rate (RR), defined as ≥50% reduction in the modified Severity Weighted Assessment Tool (mSWAT) score, of 24% (6 out of 25 evaluable patients). The overall global RR was lower at 8%. The duration of response (DOR) in the skin for responders ranged from 2.8 to 6.9 months, and the median progression-free survival (PFS) was 5.1 months. Relief from pruritus was more frequently observed in cutaneous responders (67%) compared to non-responders (32%).[29]
Pharmacodynamics: Serial tumor biopsies from treated patients showed an increase in acetylated tubulin, suggesting target engagement of HDAC6.[29]
Status: This trial is completed. However, development of Quisinostat for CTCL appears to have been discontinued.[20]
Leukemia (Advanced or Refractory):
Quisinostat was investigated for advanced or refractory leukemia, as indicated by DrugBank.[1] Preclinical studies showed activity in T-cell ALL xenograft models.[8]
A Phase I clinical trial that included patients with advanced or refractory leukemia and/or myelodysplastic syndrome was terminated.[2]
Currently, the development of Quisinostat for leukemia appears to be discontinued.[20]
Myelodysplastic Syndromes (MDS):
Similar to leukemia, MDS was an indication explored for Quisinostat.[1]
The aforementioned terminated Phase I trial also included MDS patients.[2]
Development for MDS has also been reported as discontinued.[20]
Multiple Myeloma:
Preclinical studies indicated anti-myeloma activity for Quisinostat.[12] It was investigated in Phase I/II clinical trials for this indication.[36]
However, development for multiple myeloma also appears to have been discontinued.[13]

The discontinuation of Quisinostat development for several hematological malignancies, despite some early signals of activity (e.g., in CTCL), suggests that the drug may not have achieved a sufficiently compelling efficacy-to-safety ratio in these settings, or that strategic decisions by the developers led to a reprioritization of resources. The termination of the Phase I trial for leukemia/MDS further supports this inference.[2]

Solid Tumors

Ovarian Cancer (Platinum-Resistant):
NCT02948075 was a multicenter Phase II study evaluating Quisinostat (12 mg orally on Days 1, 3, 5, 7, 9, and 11 of each 3-week cycle) in combination with paclitaxel (175 mg/m²) and carboplatin (AUC5) in patients with recurrent platinum-resistant ovarian cancer.[2]
Efficacy: This combination therapy demonstrated a notable objective response rate (ORR) of 50.0% in 30 evaluable patients. The median duration of response (DOR) was 5 months (95% CI: 4.2-5.7 months), and the median progression-free survival (PFS) was 6 months (95% CI: 4.4-7.6 months).[43]
Status: The trial is completed. AdisInsight lists Quisinostat in Phase II development for ovarian cancer.[20]
The ORR of 50% in the difficult-to-treat population of platinum-resistant ovarian cancer is a significant finding, suggesting a potential synergistic effect between Quisinostat and standard chemotherapy agents. This level of activity warrants further investigation, although the tolerability of the combination, with 71% of patients experiencing Grade 3 adverse events, requires careful consideration and management strategies in future studies.
Glioblastoma (GBM):
Strong preclinical evidence supports Quisinostat's role as a brain-penetrant radiosensitizer in GBM models.[6]
A Phase 0/Ib clinical trial, NCT06824662, is planned to evaluate Quisinostat in combination with radiotherapy for patients with newly-diagnosed and recurrent Grade 4 IDH-wildtype GBM. This trial is anticipated to begin in May 2025 in the USA.[20] This planned trial signifies a focused development effort based on Quisinostat's unique properties relevant to this challenging cancer.
Non-Small Cell Lung Cancer (NSCLC):
A Phase I trial (NCT02728492) of Quisinostat in combination with chemotherapy for NSCLC has been completed.[2]
According to AdisInsight, development for lung cancer is currently at Phase II.[20]
Preclinical studies have suggested that Quisinostat can disrupt the integrity of the epithelial barrier in lung adenocarcinoma cells.[47]
Other Solid Tumors (General "Neoplasms"):
A Phase I study of Quisinostat (JNJ-26481585) in patients with advanced solid tumors established a recommended Phase II dose of 12 mg administered on a Monday, Wednesday, Friday (MWF) schedule. In this study, one partial response was observed in a patient with melanoma, and stable disease was noted in eight other patients.[28]
However, the development of Quisinostat for "Solid Tumours" as a broad, undifferentiated category appears to have been discontinued.[20]

Table 4: Overview of Key Clinical Trials for Quisinostat

NCT Number	Phase	Indication(s)	Patient Population Key Characteristics	Quisinostat Dosage Regimen	Combination Agents	Key Efficacy Outcomes	No. of Pts	Trial Status	Reference(s)
NCT01486277	II	Cutaneous T-Cell Lymphoma (Stage IB-IVA MF/SS)	Previously treated	8mg or 12mg PO, 3x/week	Monotherapy	Cutaneous RR (mSWAT): 24%; Global RR: 8%; Median DOR (skin): 2.8-6.9 mo; Median PFS: 5.1 mo	26 (25 eval.)	Completed	29
NCT02948075	II	Recurrent Platinum-Resistant Ovarian Cancer	Tumor progression 1-6 mo after 1st line platinum/paclitaxel CT	12mg PO, Days 1,3,5,7,9,11 of 3-wk cycle	Paclitaxel, Carboplatin	ORR: 50.0%; Median DOR: 5 mo; Median PFS: 6 mo	31 (30 eval.)	Completed	43
NCT01200941 28	I	Advanced Solid Tumors	Advanced malignancies	2-12mg PO daily (continuous) or 6-19mg PO (intermittent schedules, e.g., MWF)	Monotherapy	PR: 1 melanoma pt (5 mo); SD: 8 pts (4-10.5 mo)	92	Completed	28
NCT02728492	I	Non-Small Cell Lung Cancer	Advanced/Metastatic	Not specified in snippets	Chemotherapy	Not specified in snippets	Not specified	Completed	2
Terminated Phase 1 (No NCT in snippets)	I	Advanced/Refractory Leukemia / Myelodysplastic Syndrome	Relapsed/Refractory	Not specified	Not specified	Not applicable	Not specified	Terminated	2
NCT06824662	0/Ib	Glioblastoma (Grade 4, IDH-wildtype)	Newly-diagnosed and Recurrent	Not specified in snippets	Radiotherapy	Not applicable (early phase)	30 (planned)	Planned (May 2025 start)	20

8. Safety and Tolerability Profile

Common Adverse Events (AEs)

Across various clinical trials, commonly reported treatment-emergent adverse events associated with Quisinostat include:

Gastrointestinal: Nausea, vomiting, diarrhea, decreased appetite.[3]
Constitutional: Fatigue, asthenia, lethargy.[3]
Hematological: Thrombocytopenia, neutropenia.[29]
Neurological: Neuropathy.[43]

Serious Adverse Events (SAEs) and Dose-Limiting Toxicities (DLTs)

The safety profile of Quisinostat has been characterized by notable dose-limiting toxicities, particularly cardiovascular events, which emerged during Phase I studies in patients with advanced solid tumors. These included:

Nonsustained ventricular tachycardia
ST/T-wave abnormalities on electrocardiogram (ECG)
Other tachyarhythmias
QT prolongation and atrial fibrillation have also been mentioned in the context of arrhythmia-related adverse events.[28] Reviews of HDAC inhibitors have also highlighted Grade 3 cardiac toxicities associated with Quisinostat.[13]

Non-cardiac DLTs observed in early trials included fatigue and abnormal liver function tests.28

In the Phase II trial for CTCL (NCT01486277), Grade 3 drug-related adverse events included hypertension, lethargy, pruritus, chills, hyperkalemia, and pyrexia.23

In the Phase II trial for platinum-resistant ovarian cancer (NCT02948075), where Quisinostat was used in combination with chemotherapy, SAEs were reported in 16.1% of patients. Grade 3 and Grade 4 AEs led to temporary therapy discontinuation in 71% and 48.4% of patients, respectively.43

The consistent reporting of cardiovascular toxicities as DLTs is a significant safety concern for Quisinostat. This pattern suggests a potential mechanistic link between its HDAC inhibition profile and cardiac electrophysiology or function. Such toxicities can limit the achievable therapeutic window and restrict the patient populations eligible for treatment. The observation that intermittent dosing schedules were better tolerated than continuous daily dosing in early Phase I studies [28] is a common strategy employed to manage drug-related toxicities while attempting to maintain therapeutic efficacy. This approach aims to allow for recovery periods, potentially reducing the cumulative impact of the drug on sensitive tissues like the heart.

Contraindications, Warnings, and Precautions

As Quisinostat is an investigational drug without marketing approval, official contraindications, warnings, and precautions typically found in approved drug labeling are not formally established or widely available in the provided snippets.[3] The Material Safety Data Sheet (MSDS) for JNJ-26481585 indicates that the compound is harmful if swallowed and very toxic to aquatic life with long-lasting effects. Standard laboratory handling precautions, such as avoiding inhalation, eye, and skin contact, and using adequate ventilation, are advised.[34] Given the observed DLTs, particularly cardiovascular events, careful cardiac monitoring would be an essential precaution in clinical trials.

Table 5: Summary of Common and Serious Adverse Events Associated with Quisinostat

Adverse Event Category	Specific Event(s)	Frequency/Grade	Clinical Trial Context	Reference(s)
Common AEs	Nausea, Vomiting, Diarrhea	Common	Solid Tumors, CTCL, Ovarian Cancer	23
	Fatigue, Asthenia, Lethargy	Common	Solid Tumors, CTCL	23
	Decreased Appetite	Common	Solid Tumors	28
	Thrombocytopenia	Common (22.6% in Ovarian Cancer combo)	CTCL, Ovarian Cancer	29
	Neutropenia	Common (67.7% in Ovarian Cancer combo)	Ovarian Cancer	43
	Neuropathy	Common (19.4% in Ovarian Cancer combo)	Ovarian Cancer	43
Serious AEs / DLTs	Nonsustained Ventricular Tachycardia	DLT	Advanced Solid Tumors (Phase I)	28
	ST/T-wave Abnormalities	DLT	Advanced Solid Tumors (Phase I)	28
	Other Tachyarhythmias	DLT	Advanced Solid Tumors (Phase I)	28
	QT Prolongation, Atrial Fibrillation	Arrhythmia-related AEs	Advanced Solid Tumors (Phase I)	28
	Fatigue (severe)	DLT	Advanced Solid Tumors (Phase I)	28
	Abnormal Liver Function Tests	DLT	Advanced Solid Tumors (Phase I)	28
	Hypertension	Grade 3	CTCL (Phase II)	23
	Lethargy (severe)	Grade 3	CTCL (Phase II)	23
	Pruritus (severe)	Grade 3	CTCL (Phase II)	23
	Hyperkalemia	Grade 3	CTCL (Phase II)	29

9. Drug Interactions

Interactions with Cytochrome P450 (CYP) Enzymes

Pharmacokinetic data suggest that Quisinostat has the potential to interact with several Cytochrome P450 (CYP) enzymes, which are crucial for the metabolism of many drugs:

CYP2D6: Quisinostat is an inhibitor of CYP2D6. Clinical evidence supports this interaction, with a reported IC50 value of 3.3786 µM.[23]
CYP3A4: Quisinostat is also an inhibitor of CYP3A4. However, the clinical evidence for this interaction is described as inconclusive, with an IC50 of 23.9185 µM.[23]
CYP2C9: Quisinostat is listed as an inhibitor of CYP2C9, but no clinical evidence of this interaction was reported in the cited sources.[23]

Interactions with P-glycoprotein (P-gp)

Quisinostat is an inhibitor of P-glycoprotein (P-gp, also known as multidrug resistance protein 1 or MDR1), an important efflux transporter that affects the absorption and distribution of many drugs. Clinical evidence supports this interaction, with a reported IC50 value of 1.049 µM.[23]

Clinical Significance and Management of Interactions

The inhibitory effects of Quisinostat on CYP2D6 and P-gp indicate a significant potential for drug-drug interactions (DDIs). Co-administration of Quisinostat with drugs that are substrates for CYP2D6 or P-gp could lead to increased plasma concentrations and potentially enhanced toxicity of these co-administered medications.[23] This is particularly concerning for drugs with narrow therapeutic indices. The clinical relevance of P-gp interactions can be complex, often depending on the site of interaction (e.g., gut wall, blood-brain barrier) and the pharmacokinetic properties of the co-administered drug.[64]

Given these potential interactions, a careful review of all concomitant medications is essential for patients receiving Quisinostat in clinical trials. Dose adjustments of co-administered drugs, or selection of alternative medications that are not substrates for CYP2D6 or P-gp, may be necessary to avoid adverse outcomes. The inconclusive data regarding CYP3A4 inhibition warrants further investigation, as CYP3A4 is a major enzyme involved in the metabolism of a large proportion of clinically used drugs. Understanding the full spectrum of Quisinostat's DDI potential is critical for its safe clinical development and use.

Table 6: Potential Drug Interactions of Quisinostat (CYP Enzymes, P-gp)

Enzyme/Transporter	Nature of Interaction with Quisinostat	IC50 Value	Clinical Evidence/Significance	Reference(s)
CYP2D6	Inhibitor	3.3786 µM	Yes, potential for clinically significant interactions	23
P-glycoprotein (P-gp)	Inhibitor	1.049 µM	Yes, potential for clinically significant interactions	23
CYP3A4	Inhibitor	23.9185 µM	Inconclusive	23
CYP2C9	Inhibitor	Not specified	No clinical evidence reported in source	23

10. Regulatory Status and Future Outlook

Current FDA/EMA Approval Status

As of the latest available information, Quisinostat remains an investigational drug. It has not received marketing approval from the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for any therapeutic indication.[5] The Inxight Drugs database lists Quisinostat with an "Investigational" status.[23]

Orphan Drug or Fast Track Designations

The provided research snippets do not contain information indicating that Quisinostat has received Orphan Drug designation or Fast Track designation from either the FDA or EMA for any of its investigated indications.[20] AdisInsight specifically notes "No" for Orphan Drug Status for Quisinostat.[20]

Summary of Development Landscape and Discontinued Indications

Quisinostat's clinical development has been extensive, exploring its utility across a range of cancers. According to AdisInsight (as of April 2025), the highest development phase reached is Phase II for lung cancer and ovarian cancer.20

However, development has been discontinued for several other indications, including:

Cutaneous T-cell lymphoma [20]
Leukemia [20]
Multiple Myeloma [20]
Myelodysplastic Syndromes [20]
Solid Tumors (as a general category) [20]

Despite these discontinuations, there is a renewed focus on glioblastoma. A Phase 0/Ib clinical trial (NCT06824662) is planned in the USA to evaluate Quisinostat in combination with radiotherapy for patients with newly-diagnosed and recurrent Grade 4 IDH-wildtype glioblastoma, with an anticipated start date of May 2025.[20]

Potential Future Research Directions and Unmet Needs

The strategic shift towards investigating Quisinostat in GBM, particularly in conjunction with radiotherapy, appears to be driven by its unique pharmacokinetic property of brain penetration and its potent preclinical radiosensitizing effects.[6] This targeted approach leverages the drug's strengths in an area of high unmet medical need.

The discontinuation of development in several hematological malignancies and for broad solid tumor indications, despite some early encouraging results (e.g., in CTCL or the Phase I solid tumor study), suggests that the overall risk-benefit profile may not have been sufficiently compelling in those contexts, either due to limited monotherapy efficacy or significant toxicities, especially the cardiovascular AEs.

Future research for Quisinostat is likely to focus on:

Combination Therapies: As demonstrated in the platinum-resistant ovarian cancer trial (NCT02948075) [2] and the planned GBM trial with radiotherapy, combination strategies appear to be key. Given its immunomodulatory effects on T-cells observed preclinically [18], combinations with immunotherapy could also be a viable avenue, although not explicitly detailed in the provided clinical trial information.
Well-Defined Patient Populations: Focusing on indications where its specific mechanism (e.g., potent HDAC1 inhibition) or PK properties (brain penetration) offer a distinct advantage.
Management of Cardiovascular Toxicity: Continued efforts to optimize dosing schedules (e.g., intermittent dosing) and implement robust cardiac monitoring will be crucial for any future development to manage its significant cardiovascular safety concerns.

The trajectory of Quisinostat's development underscores the complexities of bringing a pan-HDAC inhibitor to market. While broad activity is often seen preclinically, translating this into a favorable therapeutic index in diverse human cancers is challenging. The current focus on GBM in combination with radiotherapy represents a rational, mechanism-based approach that may yet define a clinical niche for Quisinostat, should the upcoming trials yield positive results.

11. Conclusion

Quisinostat (JNJ-26481585) is a second-generation, orally bioavailable hydroxamic acid-based histone deacetylase (HDAC) inhibitor with high potency, particularly against Class I HDACs such as HDAC1. Its mechanism involves inducing histone hyperacetylation, leading to chromatin remodeling, altered gene expression, apoptosis, and cell cycle arrest in cancer cells. It also affects non-histone protein acetylation, contributing to its diverse biological effects.

Preclinical studies have consistently demonstrated broad-spectrum anti-tumor activity in vitro and in vivo across various cancer types. A notable preclinical finding is its ability to penetrate the blood-brain barrier and act as a potent radiosensitizer, particularly in glioblastoma models.

Clinical development has explored Quisinostat in a range of hematological malignancies (CTCL, leukemia, MDS, multiple myeloma) and solid tumors (ovarian cancer, GBM, NSCLC). While some promising efficacy signals were observed, such as a 50% objective response rate in combination with chemotherapy for platinum-resistant ovarian cancer and a 24% cutaneous response rate in relapsed/refractory CTCL, its development has been discontinued for several of these initial indications. Challenges in achieving a consistently favorable risk-benefit profile, particularly due to dose-limiting cardiovascular toxicities (including arrhythmias and QT prolongation), have likely contributed to these decisions.

Pharmacokinetically, Quisinostat shows dose-proportional exposure and has a relatively short plasma half-life, necessitating optimized dosing schedules, often intermittent, to manage tolerability. It is an inhibitor of CYP2D6 and P-glycoprotein, indicating a potential for drug-drug interactions.

Currently, Quisinostat remains an investigational agent. The development focus appears to have strategically pivoted towards indications where its specific attributes can be best exploited, such as in GBM, where a Phase 0/Ib trial in combination with radiotherapy is planned. This approach leverages its brain penetration and radiosensitizing capabilities. The future of Quisinostat in oncology will likely depend on the success of these more targeted combination strategies and the effective management of its safety profile.

12. References

11 Probes & Drugs. Quisinostat.

1 PubChem. Compound Summary: Quisinostat.

24 Santa Cruz Biotechnology. JNJ-26481585.

25 ChemScene. Quisinostat.

19 Viriom. Oncology.

22 NewVac LLC. News.

27 Cancer Research UK. A trial of JNJ26481585 for Tcell lyphoma of skin.

45 ASH Publications. Blood. Phase 2 Multicenter Trial of Oral Quisinostat, a Histone Deacetylase Inhibitor, in Patients with Previously Treated Stage IB-IVA Cutaneous T-Cell Lymphoma.

5 National Cancer Institute. Definition of quisinostat - NCI Drug Dictionary.

6 PMC. Quisinostat is a brain-penetrant radiosensitizer in glioblastoma.

12 BOC Sciences. Quisinostat.

20 AdisInsight. Quisinostat - Janssen Pharmaceutica/NewVac.

18 AACR Journals. Cancer Research. Abstract 643: The histone deacetylase inhibitor Quisinostat augments the anti-tumor reponses of T-cells: Implications in adoptive cell therapy.

71 PMC. Class I/IIb-Selective HDAC Inhibitor Exhibits Oral.

23 Inxight Drugs. QUISINOSTAT.

43 ASCO Publications. Journal of Clinical Oncology. A multicenter phase II study of the efficacy and safety of quisinostat (an HDAC inhibitor) in combination with paclitaxel and carboplatin chemotherapy (CT) in patients (pts) with recurrent platinum resistant high grade serous epithelial ovarian, primarily peritoneal or fallopian tube carcinoma cancer (OC).

6 PubMed. Quisinostat is a brain-penetrant radiosensitizer in glioblastoma.

7 EMBL-EBI. ChEBI:94771 - quisinostat.

21 Wikipedia. Quisinostat.

49 PubMed. Quisinostat is a brain-penetrant radiosensitizer in glioblastoma. 6

28 ResearchGate. A Phase I Study of Quisinostat (JNJ-26481585), an Oral Hydroxamate Histone Deacetylase Inhibitor with Evidence of Target Modulation and Antitumor Activity, in Patients with Advanced Solid Tumors.

13 Taylor & Francis Online. A comparative safety review of histone deacetylase inhibitors for the treatment of myeloma.

46 NCATS Inxight Drugs. QUISINOSTAT. 23

26 MedChemExpress. Quisinostat - Product Data Sheet.

29 Oxford Academic. British Journal of Dermatology. Phase II multicentre trial of oral quisinostat, a histone deacetylase inhibitor, in patients with previously treated stage IB–IVA mycosis fungoides/Sézary syndrome.

50 Frontiers. Effects of entinostat, quisinostat, and tubastatin-A on alcohol consumption in male high ethanol consuming rats.

4 DrugBank. Categories: Histone Deacetylase Inhibitors. (Quisinostat entry)

1 PubChem. Compound Summary: Quisinostat. 1

10 Frontiers in Immunology. Mechanisms of HDACs in cancer development. (General review, Quisinostat not specifically detailed for non-histone targets)

6 PMC. Quisinostat is a brain-penetrant radiosensitizer in glioblastoma. 6

30 Synapse - PatSnap. Clinical Result: NCT02948075 (ASCO2017). 43

31 ResearchGate. Phase II Multicenter Trial of Oral Quisinostat, a Histone Deacetylase Inhibitor, in Patients with Previously Treated Stage IB-IVA Mycosis Fungoides/Sezary Syndrome. 29

32 Selleck Chemicals. Quisinostat (JNJ-26481585) 2HCl.

72 Oncotarget. Combining the HDAC inhibitor quisinostat with the pan-CDK inhibitor flavopiridol has a synergistic anti-tumor effect on melanoma cells.

33 HemOnc.org. Quisinostat (JNJ-26481585).

51 ResearchGate. Nano-Assembly of Quisinostat and Biodegradable Macromolecular Carrier Results in Supramolecular Complexes with Slow-Release Capabilities.

55 PMC. (Article on Nucleoside DNMTi, not directly about Quisinostat M&E)

52 Synapse - PatSnap. What HDAC1 inhibitors are in clinical trials currently?

14 ResearchGate. Quisinostat is a brain-penetrant radiosensitizer in glioblastoma. 6

34 Selleck Chemicals. MSDS_S1096.pdf (MSDS for Quisinostat).

46 NCATS Inxight Drugs. QUISINOSTAT. 23

35 American Chemical Society Publications. Radiation-Responsive Hydrogel for On-Demand Quisinostat Delivery in Glioblastoma Treatment.

36 PMC. Histone deacetylase inhibitors in cancer therapy - a review. (Table lists Quisinostat in Phase I/II for MM, solid tumors)

47 Journal of Cancer. Epigenetic modulation of the tumor microenvironment: a new frontier in non-small cell lung cancer therapy.

73 Frontiers in Immunology. Mechanisms of HDACs in cancer development. 10

20 AdisInsight. Quisinostat - Janssen Pharmaceutica/NewVac. 20

15 PMC. Combining the HDAC inhibitor quisinostat with the pan-CDK inhibitor flavopiridol has a synergistic anti-tumor effect on melanoma cells. 72

16 ResearchGate. Initial Testing (Stage 1) of the Histone Deacetylase Inhibitor Quisinostat (JNJ-26481585) by the Pediatric Preclinical Testing Program.

8 PMC. Initial Testing (Stage 1) of the Histone Deacetylase Inhibitor, Quisinostat (JNJ-26481585), by the Pediatric Preclinical Testing Program. 16

66 Rocket Pharma. Rocket Pharmaceuticals Receives FDA Fast Track and Orphan Drug Designations for RP-A601. (General FDA designation info, not Quisinostat specific)

48 Genprex. Genprex Receives U.S. FDA Fast Track Designation for REQORSA™. (General FDA designation info, not Quisinostat specific)

67 EconStor. Special FDA designations for drug development. (General FDA designation info, not Quisinostat specific)

68 Scholar Rock. Scholar Rock Receives Fast Track Designation from the U.S. FDA for Apitegromab. (General FDA/EMA designation info, not Quisinostat specific)

5 National Cancer Institute. Definition of quisinostat - NCI Drug Dictionary. 5

56 Altex. ADME - A Gating Factor for Toxicity Prediction? (General ADME review, not Quisinostat specific)

64 Medsafe NZ. P-glycoprotein and interactions with medicines. (General P-gp info)

65 PharmGKB. P-glycoprotein related drug interactions: clinical importance and. (General P-gp info)

54 Barrow Neurological Institute. Nader Sanai, MD - Selected Publications. 6

31 ResearchGate. Phase II Multicenter Trial of Oral Quisinostat... 29

37 DrugBank. Quisinostat Completed Phase 2 Trials for Cutaneous T-Cell Lymphoma (CTCL) Treatment. (Lists NCT01486277)

74 ClinicalTrials.gov. (General site information)

59 DrugBank. Quisinostat Completed Phase 2 Trials for Ovarian Cancer Treatment. (Lists NCT02948075)

63 PMC. Histone deacetylase inhibitors in ovarian cancer: an update on mechanisms of action and clinical application. (General review, mentions HDACi in ovarian cancer)

57 MedSearch Global. Clinical trials for Cancer in United States. (Lists NCT06824662)

58 DrugBank. (Lists NCT06824662 for Quisinostat in Glioblastoma)

23 NCATS Inxight Drugs. QUISINOSTAT. 23

8 PMC. Initial Testing (Stage 1) of the histone deacetylase inhibitor... 8

69 EMA. Duvyzat (givinostat) - EPAR. (Not Quisinostat)

70 EMA. New treatment against Duchenne muscular dystrophy. (Not Quisinostat)

6 PMC. Quisinostat is a brain-penetrant radiosensitizer in glioblastoma. 6

17 Spandidos Publications. Histone deacetylase inhibitor quisinostat activates caspase signaling and upregulates p53 acetylation to inhibit the proliferation of HepG2 cells.

38 PubMed. A phase I study of quisinostat (JNJ-26481585), an oral hydroxamate histone deacetylase inhibitor... 28

39 PubMed. Phase II multicentre trial of oral quisinostat, a histone deacetylase inhibitor, in patients with previously treated stage IB-IVA mycosis fungoides/Sézary syndrome. 29

9 Frontiers in Endocrinology. Protein acetylation in cancers: from mechanisms to targeted therapies. (General review on protein acetylation)

10 Frontiers in Immunology. Mechanisms of HDACs in cancer development. 10

37 DrugBank. Quisinostat Completed Phase 2 Trials for Cutaneous T-Cell Lymphoma (CTCL) Treatment. 37

75 PMC. (Article on BTK inhibitors, not Quisinostat)

59 DrugBank. Quisinostat Completed Phase 2 Trials for Ovarian Cancer Treatment. 59

63 PMC. Histone deacetylase inhibitors in ovarian cancer... 63

57 MedSearch Global. Clinical trials for Cancer in United States. 57

58 DrugBank. 58

6 PMC. Quisinostat is a brain-penetrant radiosensitizer in glioblastoma. 6

7 EMBL-EBI. ChEBI:94771 - quisinostat. 7

5 National Cancer Institute. Definition of quisinostat - NCI Drug Dictionary. 5

34 Selleck Chemicals. MSDS_S1096.pdf (MSDS for Quisinostat). 34

10 Frontiers in Immunology. Mechanisms of HDACs in cancer development. 10

53 Frontiers in Oncology Reviews. Targeting histone deacetylases in cancer: mechanisms, inhibitors, and clinical applications. (General review on HDACi)

2 DrugBank. Quisinostat.

5 National Cancer Institute. Definition of quisinostat - NCI Drug Dictionary. 5

22 NewVac LLC. News. 22

20 AdisInsight. Quisinostat - Janssen Pharmaceutica/NewVac. 20

11 Probes & Drugs. Quisinostat. 11

1 PubChem. Compound Summary: Quisinostat. 1

27 Cancer Research UK. A trial of JNJ26481585 for Tcell lyphoma of skin. 27

45 ASH Publications. Blood. Phase 2 Multicenter Trial of Oral Quisinostat... 45

6 PMC. Quisinostat is a brain-penetrant radiosensitizer in glioblastoma. 6

40 BOC Sciences. Quisinostat. 12

18 AACR Journals. Cancer Research. Abstract 643: The histone deacetylase inhibitor Quisinostat... 18

3 DrugBank. Quisinostat. (Consolidated information, used as primary source for DrugBank data)

41 ClinicalTrials.gov. (NCT01486277 - inaccessible, info from other sources)

60 ClinicalTrials.gov. (NCT02948075 - inaccessible, info from other sources)

7 EMBL-EBI. ChEBI:94771 - quisinostat. 7

20 AdisInsight. Quisinostat - Janssen Pharmaceutica/NewVac. 20

23 NCATS Inxight Drugs. QUISINOSTAT. 23

28 ResearchGate. A Phase I Study of Quisinostat (JNJ-26481585)... 28

13 Taylor & Francis Online. A comparative safety review of histone deacetylase inhibitors... 13

42 Oxford Academic. British Journal of Dermatology. Phase II multicentre trial of oral quisinostat... 29

3 DrugBank. Quisinostat. (Consolidated information, used as primary source for DrugBank data)

11 Probes & Drugs. Quisinostat. 11

6 PMC. Quisinostat is a brain-penetrant radiosensitizer in glioblastoma. 6

28 ResearchGate. A Phase I Study of Quisinostat (JNJ-26481585)... 28

42 Oxford Academic. British Journal of Dermatology. Phase II multicentre trial of oral quisinostat... 29

23 NCATS Inxight Drugs. QUISINOSTAT. 23

43 ASCO Publications. Journal of Clinical Oncology. A multicenter phase II study of the efficacy and safety of quisinostat... 43

3 DrugBank. Quisinostat. (Consolidated information, used as primary source for DrugBank data)

11 Probes & Drugs. Quisinostat. 11

6 PMC. Quisinostat is a brain-penetrant radiosensitizer in glioblastoma. 6

28 ResearchGate. A Phase I Study of Quisinostat (JNJ-26481585)... 28

23 NCATS Inxight Drugs. QUISINOSTAT. 23

43 ASCO Publications. Journal of Clinical Oncology. A multicenter phase II study of the efficacy and safety of quisinostat... 43

42 Oxford Academic. British Journal of Dermatology. Phase II multicentre trial of oral quisinostat... 29

3 DrugBank. Quisinostat. (Consolidated information, used as primary source for DrugBank data)

11 Probes & Drugs. Quisinostat. 11

6 PMC. Quisinostat is a brain-penetrant radiosensitizer in glioblastoma. 6

28 ResearchGate. A Phase I Study of Quisinostat (JNJ-26481585)... 28

23 NCATS Inxight Drugs. QUISINOSTAT. 23

43 ASCO Publications. Journal of Clinical Oncology. A multicenter phase II study of the efficacy and safety of quisinostat... 43

42 Oxford Academic. British Journal of Dermatology. Phase II multicentre trial of oral quisinostat... 29

44 ClinicalTrials.gov. (NCT01486277 - inaccessible, info from other sources)

61 ClinicalTrials.gov. (NCT02948075 - inaccessible, info from other sources)

62 ClinicalTrials.gov. (NCT06824662 - inaccessible, info from other sources)

Note: Several snippets are duplicates or provide overlapping information. Citations will prioritize the most comprehensive or primary source for a given piece of data.# Quisinostat (DB12985): A Comprehensive Review of Its Preclinical and Clinical Development as an HDAC Inhibitor in Oncology

1. Executive Summary

Developed initially by Janssen Pharmaceuticals and later co-developed in specific regions by NewVac LLC, Quisinostat has undergone extensive preclinical evaluation demonstrating broad in vitro cytotoxicity against various cancer cell lines and in vivo efficacy in several xenograft models. A notable preclinical finding is its ability to penetrate the blood-brain barrier and act as a potent radiosensitizer, particularly in glioblastoma models.

2. Introduction to Quisinostat (DB12985)

Overview and Therapeutic Rationale

Development History and Key Developers

Quisinostat was originally developed by Janssen Pharmaceuticals, a pharmaceutical company of Johnson & Johnson.[19] Subsequently, NewVac LLC, a ChemRar company and resident of the Skolkovo Innovation Center in Russia, entered into a co-licensing agreement with Janssen Pharmaceutica NV for Quisinostat.[20] This agreement granted NewVac exclusive rights for the development and commercialization of the compound in Russia and several other Eastern European countries. Under this arrangement, NewVac was responsible for conducting research and development, including supporting clinical trials within these territories, while Janssen was to contribute its expertise in global clinical trial management.[22]

3. Physicochemical Properties and Formulation

Chemical Identification

Quisinostat is recognized by its International Nonproprietary Name (INN) and US Adopted Name (USAN) as Quisinostat.[1] Its unique Chemical Abstracts Service (CAS) Registry Number is 875320-29-9.[1] In drug databases, it is cataloged under DrugBank ID DB12985.[1] The most frequently cited development code name for Quisinostat is JNJ-26481585, often used in preclinical and early clinical study reports.[1] Other identifiers include UNII: 9BJ85K1J8S, ChEBI: CHEBI:94771, and ChEMBL: CHEMBL2105763.[1]

Molecular Structure, Formula, and Weight

Quisinostat is classified chemically as a hydroxamic acid-based compound. Its structure incorporates a methylindole moiety, a piperidine ring, and a pyrimidine ring.1

The molecular formula for Quisinostat is C21H26N6O2.1 Its molecular weight is consistently reported as approximately 394.47 g/mol (or 394.5 g/mol).1 The International Union of Pure and Applied Chemistry (IUPAC) name for Quisinostat is N-hydroxy-2-(4-((((1-methyl-1H-indol-3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxamide.1

Solubility, Stability, and Known Formulations

In clinical settings, Quisinostat has been primarily administered orally, typically in capsule form, with doses such as 12 mg being used in various trial protocols.[23] The oral bioavailability of Quisinostat is a key characteristic, facilitating its administration, particularly for potentially chronic or long-term treatment regimens in cancer patients.[1]

Table 1: Key Physicochemical Properties of Quisinostat

Property	Value	Reference(s)
Official Name	Quisinostat	1
Common Synonyms	JNJ-26481585	1
CAS Number	875320-29-9	1
DrugBank ID	DB12985	1
Molecular Formula	C21H26N6O2	1
Molecular Weight	~394.47 g/mol	1
Chemical Class	Hydroxamic acid, methylindole, piperidine, pyrimidine	1
Appearance	Solid powder	12
Key Solubility	Soluble in DMSO; various co-solvent formulations for in vivo use (≥ 2.5 mg/mL)	25
Storage Conditions	Powder: -20°C; In solvent: -80°C	25

4. Mechanism of Action and Pharmacodynamics

Role as a Histone Deacetylase (HDAC) Inhibitor

Quisinostat is a potent, second-generation, hydroxamic acid-based compound that functions as an inhibitor of histone deacetylases (HDACs).[1] It is often referred to as a "pan-HDAC inhibitor" due to its activity against multiple HDAC isoforms, although it exhibits a distinct selectivity profile within the HDAC family.[11] HDACs are crucial epigenetic modulators that remove acetyl groups from lysine residues on histones and various non-histone proteins. This deacetylation process generally leads to a more compact chromatin structure, limiting the accessibility of DNA to transcription factors and thereby repressing gene expression.[6] In numerous cancers, HDAC activity is dysregulated, contributing to an oncogenic transcriptional program.

Selectivity Profile for HDAC Isoforms

Quisinostat demonstrates high potency against Class I HDACs (HDAC1, HDAC2, HDAC3) and certain Class IIb HDACs (HDAC10, HDAC11).[7] Its selectivity profile, based on reported IC50 values, is detailed in Table 2.

A defining characteristic of Quisinostat is its exceptionally high potency against HDAC1, with a reported IC50 of 0.11 nM in cell-free assays.[11] This is particularly significant because HDAC1 has been identified as an essential enzyme for the survival of glioma stem cells (GSCs) in glioblastoma (GBM), and its expression correlates with poorer prognosis in this aggressive brain tumor.[6] The potent inhibition of HDAC1 likely underpins much of Quisinostat's observed anti-tumor activity, especially in cancers like GBM, and rationalizes its investigation as a radiosensitizer in these contexts.

The drug also potently inhibits HDAC2 (IC50: 0.33 nM), HDAC10 (IC50: 0.46 nM), and HDAC11 (IC50: 0.37 nM), and shows modest potency for HDAC4 (IC50: 0.64 nM).[11] It exhibits over 30-fold selectivity against HDACs 3, 5, 8, and 9, and has the lowest reported potency for HDAC6 and HDAC7.[11] Despite a lower in vitro potency for HDAC6, target engagement, as indicated by increased acetylation of tubulin (an HDAC6 substrate), has been observed in tumor biopsies from patients with Cutaneous T-Cell Lymphoma (CTCL) treated with Quisinostat.[29] This suggests that even at clinically relevant doses, some inhibition of HDAC6 activity may occur, contributing to the drug's broader biological effects. The activity spectrum against multiple HDAC isoforms contributes to its classification as a pan-HDAC inhibitor, but this breadth of activity may also be linked to its observed toxicity profile.

Table 2: HDAC Isoform Selectivity and Potency of Quisinostat

HDAC Isoform	IC50 (nM)	Potency Description	Reference(s)
HDAC1	0.11	Highest	11
HDAC2	0.33	High	11
HDAC11	0.37	High	11
HDAC10	0.46	High	11
HDAC4	0.64	Modest	11
HDAC3	>3.3*	Low (Relatively)	11
HDAC5	>3.3*	Low (Relatively)	11
HDAC8	>3.3*	Low (Relatively)	11
HDAC9	>3.3*	Low (Relatively)	11
HDAC6	Not specified	Lowest reported potency	11
HDAC7	Not specified	Lowest reported potency	11

Note: Potency descriptions are relative based on the provided data. IC50 values for HDACs 3, 5, 8, and 9 are described as >30-fold less potent than for HDAC1, implying IC50 values >3.3 nM.

Molecular Effects

The inhibition of HDAC enzymes by Quisinostat leads to several key molecular changes:

Histone Hyperacetylation: The primary molecular consequence is the accumulation of acetyl groups on lysine residues of histone proteins (e.g., H3K9/14ac, H3K27ac). This increased acetylation neutralizes the positive charge of histones, leading to a more relaxed, open chromatin structure (euchromatin). This altered chromatin state enhances the accessibility of DNA to transcription factors and can reactivate the expression of previously silenced genes, including critical tumor suppressor genes.[1]
Impact on Non-Histone Protein Acetylation: HDACs also target a multitude of non-histone proteins involved in various cellular processes. Quisinostat-mediated HDAC inhibition can thus affect the acetylation status and function of these proteins. Examples include:
p53: Quisinostat treatment has been shown to upregulate p53 acetylation at specific lysine residues (K381/K382), reportedly by impairing the interaction between HDAC6 and p53, leading to p53 activation.[17]
HSP70 and Bcl-2: Compared to first-generation HDAC inhibitors, Quisinostat may induce superior upregulation of Heat Shock Protein 70 (HSP70) and downregulation of the anti-apoptotic protein Bcl-2.[11]
p21: It leads to the upregulation of p21 (CDKN1A), a cyclin-dependent kinase inhibitor involved in cell cycle control.[6]
Tubulin: Acetylation of α-tubulin, a substrate of HDAC6, observed in tumor biopsies following Quisinostat treatment, indicates target engagement of HDAC6.[29]
Other Proteins: Modulation of acetylation has also been reported for nucleolin, replication protein A 70 kDa DNA-binding subunit, phosphoglycerate kinase 1, stress-70 protein, the proto-oncogene Myc, and serine hydroxymethyltransferase.[7]

Cellular Consequences

The molecular effects of Quisinostat translate into several significant cellular consequences in cancer cells:

Apoptosis Induction: A primary anti-cancer effect is the induction of programmed cell death (apoptosis). This is often mediated through the activation of caspase cascades and modulation of apoptotic regulatory proteins like Bcl-2.[1]
Cell Cycle Arrest: Quisinostat can cause cancer cells to arrest at various phases of the cell cycle, commonly G1 or G2/S phase. This effect is often linked to the upregulation of cell cycle inhibitors like p21.[6]
DNA Damage and Repair Modulation: The drug has been shown to induce DNA damage, evidenced by increased levels of phosphorylated histone H2AX (γ-H2AX), a marker for DNA double-strand breaks. Furthermore, especially in combination with radiation, Quisinostat can downregulate DNA damage repair pathways, enhancing the cytotoxic effects of radiotherapy.[6]
Chromatin Remodeling and Gene Reactivation: By inducing histone hyperacetylation, Quisinostat facilitates chromatin remodeling to a more open state. This can lead to the re-expression of silenced tumor suppressor genes, contributing to its anti-neoplastic effects.[1]
Reversal of Epithelial to Mesenchymal Transition (EMT): Preclinical data indicate that Quisinostat can amplify the expression of HDAC-repressed E-cadherin, a key cell adhesion molecule. Increased E-cadherin expression is associated with the reversal of EMT, a process implicated in tumor invasion and metastasis.[2]

Target Engagement and Dose-Response Biomarkers

The pharmacodynamic effects of Quisinostat have been monitored in clinical trials using several biomarkers:

Histone Acetylation: Increased acetylation of histone H3 (specifically H3K9/14ac and H3K27ac) in readily accessible tissues such as hair follicles, skin biopsies, and peripheral blood mononuclear cells (PBMCs), as well as in tumor biopsies, has served as a key pharmacodynamic marker. This confirms systemic target engagement of HDAC enzymes by Quisinostat.[6]
Ki67 Reduction: A decrease in the proliferation marker Ki67 in skin and tumor biopsies has been observed, indicating an anti-proliferative effect consistent with the drug's mechanism.[28]
Acetylated Tubulin: In CTCL trials, an increase in acetylated tubulin in tumor biopsies was noted, suggesting target engagement of HDAC6, even if its direct inhibition by Quisinostat is less potent compared to Class I HDACs.[29]

5. Pharmacokinetics (PK)

Absorption and Bioavailability

Quisinostat is designed for oral administration and is reported to be orally bioavailable.[1]

Distribution

Metabolism and Excretion Pathways

Key Pharmacokinetic Parameters (from human studies)

Pharmacokinetic data from Phase I human studies have provided insights into Quisinostat's behavior in patients:

Dose Proportionality: The maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of Quisinostat have been shown to increase proportionally with the administered dose. This was observed for continuous daily dosing (2-12 mg) and intermittent dosing schedules (6-19 mg).[28] This dose proportionality is a favorable pharmacokinetic characteristic, as it suggests predictable and scalable exposure with dose adjustments, simplifying dose selection in clinical practice.
Steady-State Parameters for Oral Administration: Data from Inxight Drugs indicates the following steady-state parameters in Homo sapiens after once-daily oral administration [23]:
6 mg dose: Cmax ~0.828 ng/mL, AUC ~3.62 ng·h/mL, T1/2 ~2 hours.
8 mg dose: Cmax ~1.24 ng/mL, AUC ~9.77 ng·h/mL, T1/2 ~4.08 hours.
12 mg dose: Cmax ~2.155 ng/mL, AUC ~12.91 ng·h/mL, T1/2 ~2.76 hours.
Half-life (T1/2): Quisinostat is reported to have a prolonged period of half-elimination from tissues, which contributes to sustained inhibition of its target, HDAC1.[23] However, the plasma half-life values reported from steady-state oral dosing in humans are relatively short, ranging from approximately 2 to 4 hours depending on the dose.[23] This relatively short plasma half-life might necessitate frequent dosing or optimized intermittent schedules (such as the Monday, Wednesday, Friday regimen identified in Phase I studies) to maintain adequate target engagement and therapeutic concentrations over time. Nano-assembly formulations have been explored preclinically to extend the drug's half-life, with in vitro release times reported to vary from 5 to 14 days.[51]
Species-Specific Pharmacokinetic Differences: A critical finding from preclinical studies is the species-specific stability of Quisinostat. It is reported to be highly unstable in mouse plasma and brain tissue, likely due to degradation by carboxylesterases, which are highly active in rodents. In contrast, Quisinostat is significantly more stable in human plasma and brain tissue.[6] This difference is a crucial consideration for the translation of preclinical efficacy and toxicity data to human clinical trials, as drug exposure levels and duration can vary substantially between species. It underscores the importance of direct human pharmacokinetic and pharmacodynamic assessments to accurately predict clinical outcomes.

Table 3: Summary of Quisinostat Pharmacokinetic Parameters in Humans (Steady-State, Oral Administration)

Dose	Dosing Schedule	Cmax (ng/mL)	AUC (ng·h/mL)	T1/2 (hours)	Patient Population/Study Context	Reference(s)
6 mg	Once daily	0.828	3.62	2	Homo sapiens	23
8 mg	Once daily	1.24	9.77	4.08	Homo sapiens	23
12 mg	Once daily	2.155	12.91	2.76	Homo sapiens	23
2-12 mg	Continuous daily	Dose-proportional	Dose-proportional	Not specified	Advanced solid tumors	28
6-19 mg	Intermittent schedules	Dose-proportional	Dose-proportional	Not specified	Advanced solid tumors	28

6. Preclinical Evaluation

In Vitro Antitumor Activity

In Vivo Efficacy in Animal Models

Studies on Radiosensitization (e.g., in Glioblastoma)

7. Clinical Development and Efficacy

Overview of Clinical Trial Program

Hematological Malignancies

Lymphoma (Cutaneous T-Cell Lymphoma - CTCL / Mycosis Fungoides/Sézary Syndrome):
A key trial in this indication was NCT01486277, a Phase II multicenter study evaluating oral Quisinostat (8mg or 12mg, administered on days 1, 3, and 5 of each week in 21-day cycles) in patients with previously treated Stage IB-IVA Mycosis Fungoides (MF) or Sézary Syndrome (SS).[12]
Efficacy: The trial reported a cutaneous response rate (RR), defined as ≥50% reduction in the modified Severity Weighted Assessment Tool (mSWAT) score, of 24% (6 out of 25 evaluable patients). The overall global RR was lower at 8%. The duration of response (DOR) in the skin for responders ranged from 2.8 to 6.9 months, and the median progression-free survival (PFS) was 5.1 months. Relief from pruritus was more frequently observed in cutaneous responders (67%) compared to non-responders (32%).[29]
Pharmacodynamics: Serial tumor biopsies from treated patients showed an increase in acetylated tubulin, suggesting target engagement of HDAC6.[29]
Status: This trial is completed. However, development of Quisinostat for CTCL appears to have been discontinued.[20]
Leukemia (Advanced or Refractory):
Quisinostat was investigated for advanced or refractory leukemia, as indicated by DrugBank.[1] Preclinical studies showed activity in T-cell ALL xenograft models.[8]
A Phase I clinical trial that included patients with advanced or refractory leukemia and/or myelodysplastic syndrome was terminated.[3]
Currently, the development of Quisinostat for leukemia appears to be discontinued.[20]
Myelodysplastic Syndromes (MDS):
Similar to leukemia, MDS was an indication explored for Quisinostat.[1]
The aforementioned terminated Phase I trial also included MDS patients.[3]
Development for MDS has also been reported as discontinued.[20]
Multiple Myeloma:
Preclinical studies indicated anti-myeloma activity for Quisinostat.[12] It was investigated in Phase I/II clinical trials for this indication.[36]
However, development for multiple myeloma also appears to have been discontinued.[13]

Solid Tumors

Ovarian Cancer (Platinum-Resistant):
NCT02948075 was a multicenter Phase II study evaluating Quisinostat (12mg PO on Days 1,3,5,7,9,11 of a 3-week cycle) in combination with paclitaxel (175 mg/m²) and carboplatin (AUC5) in patients with recurrent platinum-resistant ovarian cancer.[2]
Efficacy: This combination therapy demonstrated a notable objective response rate (ORR) of 50.0% in 30 evaluable patients. The median duration of response (DOR) was 5 months (95% CI: 4.2-5.7 months), and the median progression-free survival (PFS) was 6 months (95% CI: 4.4-7.6 months).[43]
Status: The trial is completed. AdisInsight lists Quisinostat in Phase II development for ovarian cancer.[20]
The ORR of 50% in the difficult-to-treat population of platinum-resistant ovarian cancer is a significant finding, suggesting a potential synergistic effect between Quisinostat and standard chemotherapy agents. This level of activity warrants further investigation, although the tolerability of the combination, with 71% of patients experiencing Grade 3 adverse events, requires careful consideration and management strategies in future studies.
Glioblastoma (GBM):
Strong preclinical evidence supports Quisinostat's role as a brain-penetrant

Works cited

Quisinostat | C21H26N6O2 | CID 11538455 - PubChem, accessed May 20, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/11538455
accessed January 1, 1970, https://www.drugbank.com/drugs/DB12985
Quisinostat: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed May 20, 2025, https://go.drugbank.com/drugs/DB12985
Hydroxylamines | DrugBank Online, accessed May 20, 2025, https://go.drugbank.com/categories/DBCAT000393
Definition of quisinostat - NCI Drug Dictionary, accessed May 20, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/quisinostat
Quisinostat is a brain-penetrant radiosensitizer in glioblastoma - PMC - PubMed Central, accessed May 20, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10721329/
CHEBI:94771 - quisinostat - EMBL-EBI, accessed May 20, 2025, https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:CHEBI:94771
Initial Testing (Stage 1) of the histone deacetylase inhibitor, quisinostat (JNJ-26481585), by the Pediatric Preclinical Testing Program - PMC, accessed May 20, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4225045/
The role of protein acetylation in carcinogenesis and targeted drug discovery - Frontiers, accessed May 20, 2025, https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.972312/full
Mechanisms of HDACs in cancer development - Frontiers, accessed May 20, 2025, https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1529239/full
QUISINOSTAT (PD011142, PAWIYAYFNXQGAP-UHFFFAOYSA-N), accessed May 20, 2025, https://www.probes-drugs.org/compound/PD011142/
CAS 875320-29-9 Quisinostat - BOC Sciences, accessed May 20, 2025, https://www.bocsci.com/product/quisinostat-cas-875320-29-9-153699.html
A comparative safety review of histone deacetylase inhibitors for the ..., accessed May 20, 2025, https://www.tandfonline.com/doi/abs/10.1080/14740338.2019.1615051
(PDF) Quisinostat is a brain-penetrant radiosensitizer in glioblastoma - ResearchGate, accessed May 20, 2025, https://www.researchgate.net/publication/375827564_Quisinostat_is_a_brain-penetrant_radiosensitizer_in_glioblastoma
Combined inhibition of CDK and HDAC as a promising therapeutic strategy for both cutaneous and uveal metastatic melanoma, accessed May 20, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5814203/
Initial Testing (Stage 1) of the Histone Deacetylase Inhibitor, Quisinostat (JNJ-26481585), by the Pediatric Preclinical Testing Program - ResearchGate, accessed May 20, 2025, https://www.researchgate.net/publication/256613105_Initial_Testing_Stage_1_of_the_Histone_Deacetylase_Inhibitor_Quisinostat_JNJ-26481585_by_the_Pediatric_Preclinical_Testing_Program
Histone deacetylase inhibitor quisinostat activates caspase signaling and upregulates p53 acetylation to inhibit the proliferation of HepG2 cells - Spandidos Publications, accessed May 20, 2025, https://www.spandidos-publications.com/10.3892/mmr.2017.7355
Abstract 643: The histone deacetylase inhibitor Quisinostat ..., accessed May 20, 2025, https://aacrjournals.org/cancerres/article/74/19_Supplement/643/597895/Abstract-643-The-histone-deacetylase-inhibitor
Oncology - Viriom, accessed May 20, 2025, https://www.viriom.com/oncology
Quisinostat - Janssen Pharmaceutica/NewVac - AdisInsight - Springer, accessed May 20, 2025, https://adisinsight.springer.com/drugs/800027268
Quisinostat - Wikipedia, accessed May 20, 2025, https://en.wikipedia.org/wiki/Quisinostat
News - NewVac LLC, accessed May 20, 2025, http://www.newvac.ru/news.html
QUISINOSTAT - Inxight Drugs - ncats, accessed May 20, 2025, https://inxight.ncats.io/drug/9BJ85K1J8S
JNJ-26481585 | CAS 875320-29-9 | SCBT - Santa Cruz Biotechnology, accessed May 20, 2025, https://www.scbt.com/p/jnj-26481585-875320-29-9
875320-29-9 | Quisinostat - ChemScene, accessed May 20, 2025, https://www.chemscene.com/875320-29-9.html
Quisinostat - Product Data Sheet, accessed May 20, 2025, https://file.medchemexpress.com/batch_PDF/HY-15433/Quisinostat-DataSheet-MedChemExpress.pdf
A trial of quisinostat for T cell lymphoma of the skin | Cancer ..., accessed May 20, 2025, https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-jnj26481585-for-tcell-lyphoma-of-skin
(PDF) A Phase I Study of Quisinostat (JNJ-26481585), an Oral ..., accessed May 20, 2025, https://www.researchgate.net/publication/237060827_A_Phase_I_Study_of_Quisinostat_JNJ-26481585_an_Oral_Hydroxamate_Histone_Deacetylase_Inhibitor_with_Evidence_of_Target_Modulation_and_Antitumor_Activity_in_Patients_with_Advanced_Solid_Tumors
Phase II multicentre trial of oral quisinostat, a histone deacetylase inhibitor, in patients with previously treated stage IB–IVA mycosis fungoides/Sézary syndrome | British Journal of Dermatology | Oxford Academic, accessed May 20, 2025, https://academic.oup.com/bjd/article-abstract/175/1/80/6616976?redirectedFrom=fulltext&itm_medium=sidebar&itm_source=trendmd-widget&itm_campaign=British_Journal_of_Dermatology&itm_content=British_Journal_of_Dermatology_0
Quisinostat Hydrochloride - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 20, 2025, https://synapse-patsnap-com.libproxy1.nus.edu.sg/drug/33b4d3c096904ae38c0ad222b25ff59b
Phase II Multicenter Trial of Oral Quisinostat, a Histone Deacetylase Inhibitor, in Patients with Previously Treated Stage IB-IVA Mycosis Fungoides/Sézary Syndrome - ResearchGate, accessed May 20, 2025, https://www.researchgate.net/publication/292950670_Phase_II_Multicenter_Trial_of_Oral_Quisinostat_a_Histone_Deacetylase_Inhibitor_in_Patients_with_Previously_Treated_Stage_IB-IVA_Mycosis_FungoidesSezary_Syndrome
Quisinostat (JNJ-26481585) 2HCl | 99.62%(HPLC) | HDAC inhibitor - Selleck Chemicals, accessed May 20, 2025, https://www.selleckchem.com/products/JNJ-26481585.html
Quisinostat (JNJ-26481585) | HemOnc.org - A Hematology Oncology Wiki, accessed May 20, 2025, https://hemonc.org/wiki/Quisinostat_(JNJ-26481585)
Safety Data Sheet - Selleck Chemicals, accessed May 20, 2025, https://www.selleckchem.com/msds/MSDS_S1096.pdf
Novel Treatment for Glioblastoma Delivered by a Radiation Responsive and Radiopaque Hydrogel - Perelman School of Medicine at the University of Pennsylvania, accessed May 20, 2025, https://www.med.upenn.edu/songlab/assets/user-content/documents/AmerChemSoc_June2021.pdf
Combination Therapy With Histone Deacetylase Inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi - PubMed Central, accessed May 20, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5884928/
Quisinostat Completed Phase 2 Trials for Cutaneous T-Cell Lymphoma (CTCL) Treatment, accessed May 20, 2025, https://go.drugbank.com/drugs/DB12985/clinical_trials?conditions=DBCOND0071861&phase=2&purpose=treatment&status=completed
A phase I study of quisinostat (JNJ-26481585), an oral hydroxamate histone deacetylase inhibitor with evidence of target modulation and antitumor activity, in patients with advanced solid tumors - PubMed, accessed May 20, 2025, https://pubmed.ncbi.nlm.nih.gov/23741066/
Phase II multicentre trial of oral quisinostat, a histone deacetylase inhibitor, in patients with previously treated stage IB-IVA mycosis fungoides/Sézary syndrome - PubMed, accessed May 20, 2025, https://pubmed.ncbi.nlm.nih.gov/26836950/
accessed January 1, 1970, httpsics.com/product/quisinostat-cas-875320-29-9-153699.html
accessed January 1, 1970, https://clinicaltrials.gov/study/NCT01486277
Phase II multicentre trial of oral quisinostat, a histone deacetylase ..., accessed May 20, 2025, https://academic.oup.com/bjd/article-abstract/175/1/80/6616976
A multicenter phase II study of the efficacy and safety of quisinostat ..., accessed May 20, 2025, https://ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.5541
accessed January 1, 1970, https://classic.clinicaltrials.gov/ct2/show/NCT01486277
Phase 2 Multicenter Trial of Oral Quisinostat, a Histone Deacetylase ..., accessed May 20, 2025, https://ashpublications.org/blood/article/120/21/3676/86007/Phase-2-Multicenter-Trial-of-Oral-Quisinostat-a
QUISINOSTAT - Inxight Drugs, accessed May 20, 2025, https://drugs.ncats.io/drug/9BJ85K1J8S
Drugging the tumor microenvironment epigenome for therapeutic interventions in NSCLC, accessed May 20, 2025, https://www.jcancer.org/v16p1832.htm
Genprex Receives U.S. FDA Fast Track Designation for REQORSA™ Immunogene Therapy in Combination with Keytruda® for the Treatment of Non-Small Cell Lung Cancer, accessed May 20, 2025, https://www.genprex.com/2022/01/03/genprex-receives-u-s-fda-fast-track-designation-for-reqorsa-immunogene-therapy-in-combination-with-keytruda-for-the-treatment-of-non-small-cell-lung-cancer/
Quisinostat is a brain-penetrant radiosensitizer in glioblastoma - PubMed, accessed May 20, 2025, https://pubmed.ncbi.nlm.nih.gov/37991020/
Effects of entinostat, quisinostat, and tubastatin-A on alcohol consumption in male high ethanol consuming rats - Frontiers, accessed May 20, 2025, https://www.frontiersin.org/journals/epigenetics-and-epigenomics/articles/10.3389/freae.2024.1503093/epub
(PDF) Nano-Assembly of Quisinostat and Biodegradable Macromolecular Carrier Results in Supramolecular Complexes with Slow-Release Capabilities - ResearchGate, accessed May 20, 2025, https://www.researchgate.net/publication/355886886_Nano-Assembly_of_Quisinostat_and_Biodegradable_Macromolecular_Carrier_Results_in_Supramolecular_Complexes_with_Slow-Release_Capabilities
What HDAC1 inhibitors are in clinical trials currently? - Patsnap Synapse, accessed May 20, 2025, https://synapse.patsnap.com/article/what-hdac1-inhibitors-are-in-clinical-trials-currently
Research Progress on the Mechanism of Histone Deacetylases in Ferroptosis of Glioma, accessed May 20, 2025, https://www.frontiersin.org/journals/oncology-reviews/articles/10.3389/or.2024.1432131/full
Nader Sanai, MD | Barrow Neurological Institute, accessed May 20, 2025, https://www.barrowneuro.org/person/nader-sanai-md/
Epigenetic drugs in cancer therapy - PMC - PubMed Central, accessed May 20, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11865116/
Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods | ALTEX, accessed May 20, 2025, https://www.altex.org/index.php/altex/article/view/136
Clinical Trial Studies To Participate Related To Conditions Of Cancer in United States, accessed May 20, 2025, https://medsearchglobal.com/antistudylist?condition=Cancer&country=United%20States&_token=bhst67C7klUKed9gobn2HfiJmeRtBRYjcbshYRxq&page=55
Quisinostat Not Yet Recruiting Phase 0 Trials for Glioblastoma, accessed May 20, 2025, https://go.drugbank.com/drugs/DB12985/clinical_trials?conditions=DBCOND0064153&phase=0&purpose=treatment&status=not_yet_recruiting
Quisinostat Completed Phase 2 Trials for Ovarian Cancer Treatment | DrugBank Online, accessed May 20, 2025, https://go.drugbank.com/drugs/DB12985/clinical_trials?conditions=DBCOND0028213&phase=2&purpose=treatment&status=completed
accessed January 1, 1970, https://clinicaltrials.gov/study/NCT02948075
accessed January 1, 1970, https://classic.clinicaltrials.gov/ct2/show/NCT02948075
accessed January 1, 1970, https://clinicaltrials.gov/study/NCT06824662
Potential of histone deacetylase inhibitors for the therapy of ovarian cancer - PMC, accessed May 20, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9732372/
Medicines interactions: the role of P-glycoprotein - Medsafe, accessed May 20, 2025, https://www.medsafe.govt.nz/profs/puarticles/p-glycoproteinsept2011.htm
P-glycoprotein related drug interactions: clinical importance and a consideration of disease states. - PharmGKB, accessed May 20, 2025, https://www.pharmgkb.org/pmid/20397967
Rocket Pharmaceuticals Receives FDA Fast Track and Orphan Drug Designations for RP-A601 Gene Therapy for PKP2 Arrhythmogenic Cardiomyopathy (ACM), accessed May 20, 2025, https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-receives-fda-fast-track-and-orphan-drug/
Special FDA designations for drug development: orphan, fast track, accelerated approval, priority review, and breakthrough therapy - EconStor, accessed May 20, 2025, https://www.econstor.eu/bitstream/10419/313344/1/s10198-023-01639-x.pdf
Scholar Rock Receives Fast Track Designation from the U.S. FDA for Apitegromab for the Treatment of Patients with Spinal Muscular Atrophy, accessed May 20, 2025, https://investors.scholarrock.com/news-releases/news-release-details/scholar-rock-receives-fast-track-designation-us-fda-apitegromab/
Duvyzat | European Medicines Agency (EMA), accessed May 20, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/duvyzat
New treatment against Duchenne muscular dystrophy | European Medicines Agency (EMA), accessed May 20, 2025, https://www.ema.europa.eu/en/news/new-treatment-against-duchenne-muscular-dystrophy
Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia - PMC, accessed May 20, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6956385/
Combined inhibition of CDK and HDAC as a promising therapeutic strategy for both cutaneous and uveal metastatic melanoma | Oncotarget, accessed May 20, 2025, https://www.oncotarget.com/article/23485/text/
Mechanisms of HDACs in cancer development - Frontiers, accessed May 20, 2025, https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1529239/epub
ClinicalTrials.gov: Home, accessed May 20, 2025, https://clinicaltrials.gov/
Pharmacologic Targeting of the Cancer Epigenome - PMC - PubMed Central, accessed May 20, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11936478/

Quisinostat Advanced Drug Monograph

Generic Name

Drug Type

Chemical Formula

CAS Number

Quisinostat (DB12985): A Comprehensive Review of Its Preclinical and Clinical Development as an HDAC Inhibitor in Oncology

1. Executive Summary

2. Introduction to Quisinostat (DB12985)

Overview and Therapeutic Rationale

Development History and Key Developers

3. Physicochemical Properties and Formulation

Chemical Identification

Molecular Structure, Formula, and Weight

Solubility, Stability, and Known Formulations

4. Mechanism of Action and Pharmacodynamics

Role as a Histone Deacetylase (HDAC) Inhibitor

Selectivity Profile for HDAC Isoforms

Molecular Effects

Cellular Consequences

Target Engagement and Dose-Response Biomarkers

5. Pharmacokinetics (PK)

Absorption and Bioavailability

Distribution

Metabolism and Excretion Pathways

Key Pharmacokinetic Parameters (from human studies)

6. Preclinical Evaluation

In Vitro Antitumor Activity

In Vivo Efficacy in Animal Models

Studies on Radiosensitization (e.g., in Glioblastoma)

7. Clinical Development and Efficacy

Overview of Clinical Trial Program

Hematological Malignancies

Solid Tumors

8. Safety and Tolerability Profile

Common Adverse Events (AEs)

Serious Adverse Events (SAEs) and Dose-Limiting Toxicities (DLTs)

Contraindications, Warnings, and Precautions

9. Drug Interactions

Interactions with Cytochrome P450 (CYP) Enzymes

Interactions with P-glycoprotein (P-gp)

Clinical Significance and Management of Interactions

10. Regulatory Status and Future Outlook

Current FDA/EMA Approval Status

Orphan Drug or Fast Track Designations

Summary of Development Landscape and Discontinued Indications

Potential Future Research Directions and Unmet Needs

11. Conclusion

12. References

1. Executive Summary

2. Introduction to Quisinostat (DB12985)

Overview and Therapeutic Rationale

Development History and Key Developers

3. Physicochemical Properties and Formulation

Chemical Identification

Molecular Structure, Formula, and Weight

Solubility, Stability, and Known Formulations

4. Mechanism of Action and Pharmacodynamics

Role as a Histone Deacetylase (HDAC) Inhibitor

Selectivity Profile for HDAC Isoforms

Molecular Effects

Cellular Consequences

Target Engagement and Dose-Response Biomarkers

5. Pharmacokinetics (PK)

Absorption and Bioavailability

Distribution

Metabolism and Excretion Pathways

Key Pharmacokinetic Parameters (from human studies)

6. Preclinical Evaluation

In Vitro Antitumor Activity

In Vivo Efficacy in Animal Models

Studies on Radiosensitization (e.g., in Glioblastoma)

7. Clinical Development and Efficacy

Overview of Clinical Trial Program

Hematological Malignancies

Solid Tumors

Works cited