Exisulind (Sulindac Sulfone): A Comprehensive Monograph on a Selective Apoptotic Anti-neoplastic Drug—From Preclinical Promise to Clinical Setbacks and Potential Repurposing

Executive Summary

Exisulind, known chemically as sulindac sulfone, is the primary oxidative metabolite of the non-steroidal anti-inflammatory drug (NSAID) sulindac.[1] It was developed as the lead compound in a novel class of agents termed Selective Apoptotic Anti-neoplastic Drugs (SAANDs), distinguished by an anticancer mechanism deliberately separated from the cyclooxygenase (COX) inhibition characteristic of its parent compound.[2] The core mechanism of Exisulind involves the inhibition of cyclic guanosine monophosphate phosphodiesterases (cGMP-PDEs), particularly isoforms PDE2 and PDE5.[5] This inhibition leads to a sustained elevation of intracellular cGMP, which in turn activates protein kinase G (PKG). Activated PKG promotes programmed cell death (apoptosis) through downstream pathways, including the degradation of oncogenic β-catenin and activation of the c-Jun NH2-terminal kinase (JNK) pathway.[5]

The drug underwent an extensive clinical development program investigating its potential as both a chemopreventive and therapeutic agent across several cancers. The most promising signals of efficacy were observed in familial adenomatous polyposis (FAP) and prostate cancer. In FAP, clinical trials demonstrated that Exisulind could significantly reduce the formation of precancerous colorectal polyps.[3] In patients with biochemically recurrent prostate cancer, it significantly slowed the rate of rise in prostate-specific antigen (PSA) levels.[9] In contrast, multiple combination trials in non-small cell lung cancer (NSCLC) failed to show any benefit over standard chemotherapy, despite strong preclinical evidence of synergy.[10]

Ultimately, the clinical development of Exisulind for its primary indications was halted. Despite promising efficacy, the drug exhibited a narrow therapeutic window, with dose-limiting hepatotoxicity emerging as the critical safety concern.[12] The dose required for consistent therapeutic effect was too close to the dose that caused unacceptable, albeit reversible, liver enzyme elevations, rendering its risk-benefit profile unfavorable for long-term chemoprevention. This led to the U.S. Food and Drug Administration (FDA) issuing a "non-approvable" letter for the FAP indication in 2000.[3]

Despite these setbacks, Exisulind remains a molecule of significant scientific interest. Its development journey offers critical lessons in targeted therapy and the challenges of clinical translation. More recently, its unique mechanism of action has led to a potential new application. In 2014, the European Medicines Agency (EMA) granted Exisulind orphan designation for the treatment of familial cerebral cavernous malformations (FCCM), a rare vascular disease also linked to β-catenin dysregulation.[1] Exisulind thus stands as an unapproved but important investigational agent, illustrating the complex interplay between targeted efficacy, therapeutic index, and the potential for mechanism-based drug repurposing.

Drug Profile and Chemical Characteristics

Classification and Origin

Exisulind is an investigational small molecule drug that represents the prototype of a class known as Selective Apoptotic Anti-neoplastic Drugs (SAANDs).[2] Its development was pioneered by Cell Pathways, which was later acquired by OSI Pharmaceuticals.[3] Chemically, Exisulind is the sulfone metabolite of the widely used NSAID, sulindac.[1] It is formed in the body through the irreversible oxidation of its parent compound.[17] This metabolic relationship is fundamental to its design, as the conversion to the sulfone form strips the molecule of the anti-inflammatory and COX-inhibitory activities associated with sulindac, thereby isolating its distinct anti-neoplastic properties.[4]

Nomenclature and Identifiers

Throughout its long history of research and development, Exisulind has been referred to by numerous names and codes. Its non-proprietary name is Exisulind, while its most common chemical name is sulindac sulfone.[1] Tentative trade names included Aptosyn and Prevatac.[3] It was also identified by several research and development codes, most notably FGN-1 and CP 248.[1] Its unique identity is cataloged across major chemical and pharmacological databases through specific registry numbers, including its CAS Number, 59973-80-7, and its DrugBank ID, DB06246.[1]

Chemical and Physical Properties

Exisulind is a yellow crystalline powder.[19] Its chemical formula is $C_{20}H_{17}FO_{4}S$, with an average molecular weight of 372.41 g/mol and a monoisotopic mass of 372.083158364 Da.[2] The formal IUPAC name is 2-[(3Z)-6-fluoro-2-methyl-3-[(4-methylsulfonylphenyl)methylidene]inden-1-yl]acetic acid.[1] As a monocarboxylic acid, it is slightly acidic with a pKa of 4.33.[21] Its solubility profile shows that it is freely soluble in alcohol and polyethylene glycol but only slightly soluble in water.[20] This limited aqueous solubility is reflected in its calculated partition coefficient (XLogP3) of 3.5, indicating a lipophilic nature.[1]

Table 1: Chemical and Physical Identifiers of Exisulind

Identifier Type	Value	Source(s)
Generic Name	Exisulind	1
Synonyms	Sulindac sulfone, Aptosyn, Prevatac, FGN-1	3
CAS Number	59973-80-7	1
DrugBank ID	DB06246	2
IUPAC Name	2-[(3Z)-6-fluoro-2-methyl-3-[(4-methylsulfonylphenyl)methylidene]inden-1-yl]acetic acid	1
Molecular Formula	$C_{20}H_{17}FO_{4}S$	2
Molecular Weight	372.41 g/mol (Average)	2
SMILES	CC\1=C(C2=C(/C1=C\C3=CC=C(C=C3)S(=O)(=O)C)C=CC(=C2)F)CC(=O)O	1
InChIKey	MVGSNCBCUWPVDA-MFOYZWKCSA-N	1
Physical Appearance	Yellow crystalline powder / Yellow solid	19
pKa	4.33 (acidic)	21
Solubility	Slightly soluble in water; freely soluble in alcohol	20

Mechanism of Action: A COX-Independent Pathway to Apoptosis

The Paradigm Shift from NSAID to SAAND

The central therapeutic concept behind Exisulind was to harness the observed anti-cancer properties of NSAIDs like sulindac while circumventing their dose-limiting toxicities.[4] Chronic NSAID use is associated with serious gastrointestinal and renal adverse events, which are directly attributable to the inhibition of cyclooxygenase (COX) enzymes and the subsequent disruption of prostaglandin synthesis.[8] Exisulind was specifically identified as the metabolite of sulindac that lacks meaningful COX-1 or COX-2 inhibitory activity.[1] Its ability to induce apoptosis is therefore independent of prostaglandin pathways and also operates separately from other common cancer pathways involving p53 or Bcl-2, establishing it as a new class of agent with a novel mechanism.[3]

Primary Molecular Target: cGMP Phosphodiesterase (PDE) Inhibition

The core of Exisulind's mechanism is the inhibition of cyclic guanosine monophosphate phosphodiesterases (cGMP-PDEs), a family of enzymes that degrade the second messenger cGMP.[2] Research has shown that Exisulind inhibits isoforms from the PDE2 and PDE5 gene families, which are frequently overexpressed in neoplastic tissues.[5] For instance, in human bladder tumor cells, Exisulind demonstrated inhibitory activity against PDE5 and PDE4 with 50% inhibitory concentrations ($IC_{50}$) of 112 µM and 116 µM, respectively.[7]

The Cellular Cascade: cGMP Elevation and PKG Activation

By inhibiting the enzymes responsible for cGMP breakdown, Exisulind treatment leads to a persistent and sustained elevation of intracellular cGMP levels.[5] This accumulation of cGMP is the critical initiating event in the drug's signaling cascade. Elevated cGMP, in turn, acts as an allosteric activator for cGMP-dependent protein kinase G (PKG).[2] The activation of PKG is the pivotal step that translates the upstream enzymatic inhibition into downstream cellular effects culminating in apoptosis.[20]

Downstream Apoptotic Triggers

Once activated, PKG phosphorylates key cellular substrates that regulate cell survival and proliferation. Two primary downstream effects have been identified:

1. β-Catenin Degradation: PKG directly phosphorylates β-catenin, a protein that, when dysregulated, acts as a potent oncogene.[5] This phosphorylation event marks β-catenin for ubiquitination and subsequent degradation by the proteasome.[20] This mechanism is particularly relevant for colorectal cancer, especially in the context of FAP. The hallmark of FAP is a mutation in the APC gene, which normally functions to suppress β-catenin levels. In FAP patients, this suppression fails, leading to an accumulation of β-catenin that drives uncontrolled cell proliferation and polyp formation.[5] Exisulind's ability to promote β-catenin degradation directly counteracts the fundamental molecular defect of this hereditary disease. This provides a clear, rational basis for the strong efficacy signals observed in FAP clinical trials, where the drug was shown to effectively reduce polyp formation.[3]
2. JNK Pathway Activation: In addition to its effects on β-catenin, PKG activation has been shown to stimulate the c-Jun NH2-terminal kinase (JNK) signaling pathway, a well-established mediator of cellular stress responses and a potent inducer of apoptosis.[6]

Selectivity for Neoplastic Cells

The therapeutic potential of Exisulind hinges on its ability to selectively target cancer cells while sparing normal tissues. This selectivity is believed to arise from the biological context of its target. The cGMP-PDE enzymes that Exisulind inhibits are significantly overexpressed in many precancerous and cancerous tissues compared to their normal counterparts.[2] This differential expression creates a therapeutic window: at clinically achievable concentrations, Exisulind can effectively inhibit the overabundant PDEs in tumor cells to trigger apoptosis, while the lower levels of the enzyme in normal cells are less affected, thus preserving their viability.[20]

Ancillary Mechanisms

In addition to its primary pro-apoptotic mechanism, Exisulind has been shown to exert other anti-cancer effects. Preclinical studies have provided evidence that it can inhibit angiogenesis, the formation of new blood vessels that tumors require to grow.[3] This effect may also be linked to the PKG pathway, which has been shown to down-regulate the expression of vascular endothelial growth factor (VEGF).[29] Furthermore, Exisulind is a potent inhibitor of aldose reductase (AKR1B1), an enzyme involved in the polyol pathway, with an $IC_{50}$ of 367 nM.[2] While primarily studied in the context of diabetic complications, this activity may contribute to its overall cellular effects.

Pharmacokinetic Profile

Absorption

Exisulind is formulated for oral administration.[12] While comprehensive absorption data for Exisulind itself is limited in the available literature, studies of more potent structural analogs provide insight into the class. For example, the related SAAND, CP-461, demonstrated rapid absorption, with maximum plasma concentrations ($T_{max}$) achieved between 1 to 2 hours after dosing.[32]

Distribution

Specific data regarding the volume of distribution and plasma protein binding of Exisulind are not detailed in the provided materials. However, its parent drug, sulindac, is known to be highly protein-bound, a characteristic common to many NSAIDs and their derivatives.[33]

Metabolism

The metabolism of Exisulind is intrinsically linked to its origin. It is not a primary drug but rather an active metabolite of sulindac.[1] After oral administration, sulindac, which is a sulfoxide, undergoes extensive biotransformation in the body. This includes a reversible reduction to sulindac sulfide (the primary COX-inhibiting, anti-inflammatory metabolite) and an irreversible oxidation to sulindac sulfone (Exisulind), the COX-sparing, pro-apoptotic agent.[4] The complex interplay between these metabolic pathways, which may include enterohepatic recirculation, complicates the overall pharmacokinetic profile.[34]

Elimination and Half-Life

The primary route of elimination for Exisulind appears to be renal. Following administration of sulindac, approximately half of the dose is excreted in the urine, largely in the form of conjugated Exisulind.[1] Clinical studies in patients with FAP determined the serum half-life ($t_{1/2}$) of Exisulind to be in the range of 6 to 9 hours.[12] This pharmacokinetic parameter is consistent with the twice-daily (BID) dosing schedules used in the majority of its clinical trials and suggests that little drug accumulation occurs with repeated dosing.[12]

The development of Exisulind appears to have been pursued without a complete, early-stage characterization of its absorption, distribution, metabolism, and excretion (ADME) profile. A comprehensive population pharmacokinetic model for sulindac and its metabolites was only described much later, underscoring the complexity of its disposition.[34] This lack of a complete initial understanding of Exisulind's own pharmacokinetic behavior may have posed a challenge during its clinical development. Given that its dose-limiting toxicity was hepatic and that a relationship between plasma concentration and adverse events was observed, an incomplete grasp of its ADME properties could have made it difficult to precisely model the therapeutic window and effectively manage the risk of hepatotoxicity in large-scale trials.[6]

The Clinical Development of Exisulind: A Multi-Indication Investigation

Exisulind was the subject of a broad and ambitious clinical development program, exploring its utility in the prevention and treatment of multiple cancers. The outcomes of these trials varied significantly by indication, painting a complex picture of its therapeutic potential.

A. Chemoprevention in Colorectal Neoplasia

The initial and most promising application for Exisulind was in the prevention of colorectal cancer, focusing on patients with hereditary and sporadic precancerous polyps.

Familial Adenomatous Polyposis (FAP)

This was the lead indication for Exisulind. A Phase I trial in FAP patients successfully established a maximum tolerated dose (MTD) of 300 mg twice daily. The dose-limiting toxicity was reversible hepatic dysfunction, which occurred at a dose of 400 mg twice daily.[12] Subsequent Phase II and III trials provided strong evidence of efficacy. A one-year extension of a pivotal Phase III trial demonstrated that Exisulind significantly reduced the formation of new polyps in FAP patients.[3] These positive findings were the cornerstone of the New Drug Application (NDA) submitted to the FDA.[3]

Sporadic Colonic Adenomas

Following the success in FAP, Exisulind was evaluated for the regression of sporadic adenomas in the general population. A large, multicenter, placebo-controlled Phase III trial was completed.[3] A 12-month dose-response study within this program found that a daily dose of 400 mg Exisulind led to a statistically significant regression of sporadic adenomas compared to placebo.[8] However, this efficacy was accompanied by a higher incidence of toxicity, particularly elevated liver enzymes and abdominal pain, foreshadowing the safety concerns that would ultimately derail its approval.[36]

B. Prostate Cancer

Exisulind was extensively studied in various stages of prostate cancer, from preventing recurrence to treating advanced disease.

Biochemical Recurrence

A key randomized, placebo-controlled trial investigated Exisulind (250 mg twice daily for 12 months) in 96 men who had rising PSA levels after a radical prostatectomy, indicating biochemical recurrence.[9] The results were statistically significant: Exisulind suppressed the rate of PSA increase compared to placebo, with a particularly strong effect in patients at high risk for developing metastatic disease. Furthermore, it significantly lengthened the PSA doubling time in this high-risk group.[9] The drug was reported to be well tolerated in this study.[9]

Neoadjuvant Therapy

Several Phase II trials, including NCT00078910 and NCT00166478, were conducted to assess the biological activity of Exisulind when given as a neoadjuvant treatment for approximately four weeks before a planned radical prostatectomy.[16] While one study confirmed that the drug was well-tolerated with minimal side effects, it failed to demonstrate a significant increase in apoptosis in the prostate tissue at the dose and duration tested, suggesting limited preoperative activity.[39]

C. Non-Small Cell and Small Cell Lung Cancer (NSCLC/SCLC)

Based on strong preclinical data showing tumor growth inhibition and synergistic activity with chemotherapy, particularly taxanes, a large program of clinical trials was initiated in lung cancer.[6] Exisulind was tested in combination with a wide array of standard-of-care agents, including docetaxel, paclitaxel, carboplatin, vinorelbine, gemcitabine, and etoposide.[3]

Despite the compelling preclinical rationale, the clinical outcomes in lung cancer were uniformly negative. This disconnect between laboratory findings and patient outcomes represents a significant challenge in oncology drug development. The strong evidence of synergy in animal models, which justified the extensive and costly clinical program, did not translate into a tangible benefit for patients. A Phase II study combining Exisulind with weekly docetaxel for second-line treatment of NSCLC reported no objective responses and was terminated for futility.[10] Similarly, a large Phase I/II trial of Exisulind with a docetaxel and carboplatin combination in metastatic NSCLC found that adding Exisulind did not improve the response rate, duration of response, or overall survival compared to historical data for the chemotherapy doublet alone.[11] The investigators concluded that further development of Exisulind in this setting was not warranted.[11] This failure may be attributable to a number of factors, including species-specific differences in pharmacology, an inability to achieve synergistic drug concentrations in human tumors without causing unacceptable toxicity, or complexities of the human tumor microenvironment not captured by preclinical models.

Table 2: Summary of Key Clinical Trials for Exisulind

Indication	Trial Phase	Reference / NCT ID	Intervention	Primary Outcome(s)	Key Result Summary
Familial Adenomatous Polyposis (FAP)	Phase I	van Stolk R, et al. 2000	Exisulind 200-400 mg BID	MTD, Safety	MTD established at 300 mg BID; DLT was reversible hepatotoxicity. 12
FAP	Phase III (Extension)	Cell Pathways Announcement	Exisulind	New polyp formation	Significantly reduced new polyp formation over 24 months. 3
Sporadic Colonic Polyps	Phase III	Arber N, et al. 2005	Exisulind 400 mg/day vs. Placebo	Polyp size regression	Significant regression of adenomas, but associated with increased toxicity. 8
Prostate Cancer (Biochemical Recurrence)	Phase II/III	Goluboff ET, et al. 2001	Exisulind 250 mg BID vs. Placebo	Change in PSA	Significantly suppressed PSA increase and lengthened PSA doubling time. 9
Prostate Cancer (Neoadjuvant)	Phase II	NCT00078910	Exisulind prior to prostatectomy	Apoptosis in tumor tissue	Well tolerated but no significant effect on apoptotic biomarkers. 38
NSCLC (2nd Line)	Phase II	Hanna N, et al. 2007	Exisulind + Docetaxel	Objective Response Rate (ORR)	No objective responses; trial deemed inactive. 10
NSCLC (1st Line, Metastatic)	Phase I/II	Treat J, et al. 2005	Exisulind + Docetaxel/Carboplatin	ORR, Survival	ORR 23%; no apparent enhancement of activity or survival vs. historical controls. 11

Safety, Tolerability, and Risk Profile

General Tolerability

Across multiple clinical trials, Exisulind was often described as being generally well tolerated, with most adverse events being mild to moderate in severity and reversible upon dose reduction or discontinuation.[9] This was particularly noted in studies involving patients with prostate cancer, where the safety profile appeared favorable.[9]

Commonly Reported Adverse Events

The most consistently reported side effects were gastrointestinal in nature. These included dyspepsia (indigestion), nausea, vomiting, and abdominal pain.[6] Other common non-hematologic toxicities included fatigue, anorexia, and headache.[11]

Dose-Limiting Hepatotoxicity

The critical safety issue that defined Exisulind's clinical trajectory and ultimately prevented its approval was dose-limiting hepatotoxicity.[13] In clinical trials, reversible and typically asymptomatic elevations in liver function tests (transaminases) were consistently identified as the primary dose-limiting toxicity.[6] The Phase I study in FAP patients clearly established this, where four of six patients treated at the 400 mg twice-daily dose level experienced this effect, leading to the establishment of the MTD at 300 mg twice daily.[12]

This created a significant challenge for its development as a chemopreventive agent. A primary goal in designing Exisulind was to create a safer alternative to its parent NSAID, sulindac, by eliminating the COX-mediated gastrointestinal toxicities.[8] While this objective was largely met, the molecule's own intrinsic hepatotoxicity emerged as a new, insurmountable barrier. The dose required to achieve a consistent and statistically significant reduction in colorectal polyps was found to be too close to the dose that caused an unacceptable level of liver toxicity.[13] For a drug intended for long-term use in a preventative setting, where patients are otherwise healthy, the tolerance for potential organ damage is extremely low. This unfavorable therapeutic index made the overall risk-benefit assessment untenable for the FAP indication.

Clinically Significant Drug Interactions

Pharmacological data indicate several potential drug-drug interactions for Exisulind:

• Methemoglobinemia: There is a stated risk of an increased incidence or severity of methemoglobinemia when Exisulind is combined with a wide range of drugs, most notably local anesthetics such as benzocaine, lidocaine, bupivacaine, and ropivacaine, as well as other agents like meloxicam.[2]
• Thrombosis: The risk of thrombotic events may be elevated when Exisulind is used concomitantly with erythropoiesis-stimulating agents, including darbepoetin alfa and erythropoietin.[2]
• Pharmacokinetic Interactions: In the context of combination chemotherapy for lung cancer, clinical studies found no evidence of a significant pharmacokinetic interaction between Exisulind and the cytotoxic agents docetaxel and carboplatin.[11]

Regulatory History and Current Status

The US FDA Pathway for FAP

Exisulind's journey with the U.S. Food and Drug Administration (FDA) was focused on the FAP indication and was marked by early promise followed by a definitive regulatory setback.

• Orphan Drug Designation: Recognizing the high unmet need in FAP, the FDA granted Exisulind Orphan Drug Designation on February 14, 1994, for the "suppression and control of colonic adenomatous polyps in the inherited disease adenomatous polyposis coli".[43]
• Fast Track Designation: The program was further expedited with a Fast Track designation in July 1998, reflecting the seriousness of the condition and the drug's potential to address it.[3]
• NDA Submission and Rejection: Following positive Phase III trial results, the developer, Cell Pathways, submitted a New Drug Application (NDA) in August 1999.[3] However, in September 2000, the FDA issued a "non-approvable" letter. The agency cited deficiencies in the submitted safety and efficacy data, effectively halting the drug's path to market for this indication.[3] To date, Exisulind is not approved by the FDA for any indication.[43]

The European Medicines Agency (EMA) Pathway for FCCM

Years after its development for cancer was largely abandoned, Exisulind found a potential new life through a regulatory pathway in Europe for a different disease.

• Orphan Designation: On December 16, 2014, the European Commission granted Exisulind orphan designation (EU/3/14/1387) for the treatment of familial cerebral cavernous malformations (FCCM).[1]
• Mechanistic Rationale: This designation was not arbitrary but was based on a shared molecular pathology. The abnormal growth of blood vessels in FCCM is thought to be driven by excess β-catenin signaling within the vessel walls. The known mechanism of Exisulind—inhibiting PDE5 to activate PKG and promote β-catenin degradation—provided a strong scientific rationale for its potential therapeutic effect in this rare neurological disorder.[15]
• Developmental Stage: At the time the designation was granted, the effects of Exisulind in FCCM had only been evaluated in experimental models, and no clinical trials in patients with the condition had yet been initiated.[15]

Current Global Status

Exisulind remains an investigational drug. It has not received marketing authorization from any major regulatory body worldwide for any clinical indication. Its primary value today lies in its role as a pioneering SAAND and a chemical probe for studying the cGMP-PKG signaling pathway. It continues to serve as a lead compound for the design of next-generation PDE inhibitors with potentially improved safety profiles.[29]

Synthesis and Future Outlook

Analysis of the Risk-Benefit Profile

The clinical story of Exisulind is a clear illustration of the critical importance of the therapeutic index in drug development. For its primary chemoprevention indications—FAP and sporadic polyps—the drug faced an insurmountable risk-benefit challenge. The dose required to achieve consistent and meaningful polyp regression was inseparable from the dose that produced an unacceptable rate of hepatotoxicity.[8] In a preventative setting, where therapy is administered long-term to individuals who are not yet diagnosed with invasive cancer, the tolerance for significant organ toxicity is exceptionally low. The benefit of delaying or preventing polyps could not outweigh the risk of liver damage, leading to the unfavorable regulatory outcome.

Lessons from the Clinical Development Program

The extensive investigation of Exisulind provides several key takeaways for pharmaceutical research:

1. Validation of a Targeted Mechanism: The drug successfully validated its proposed mechanism of action. It demonstrated clear biological activity in diseases where its molecular target, the cGMP-PKG-β-catenin axis, is a known driver of pathology, as seen in FAP and prostate cancer.[5]
2. The Challenge of Clinical Translation: The failure of the lung cancer program serves as a stark reminder that even strong preclinical evidence of synergy does not guarantee clinical success. The complexities of human pharmacology and tumor biology can often lead to a disconnect between results in animal models and outcomes in patients.[11]
3. The Primacy of Safety: Ultimately, Exisulind's development demonstrates that a compelling mechanism and promising efficacy signals cannot overcome a challenging safety profile. Safety, particularly in non-metastatic or preventative contexts, remains the paramount consideration for regulatory approval.

Potential for Repurposing: The Case of Familial Cerebral cavernous malformations (FCCM)

The EMA's orphan designation for FCCM represents a scientifically astute attempt to repurpose Exisulind by leveraging its known mechanism against a new disease with a shared molecular pathology.[15] This move also highlights a crucial strategic consideration in drug development: the context of the disease profoundly alters the risk-benefit calculus. The FDA's rejection for FAP occurred in a setting where an effective, albeit invasive, preventative option (colectomy) exists, making the safety bar for a new drug extremely high. In contrast, FCCM is a life-threatening condition with no approved medical therapies; the only interventions are symptomatic management or high-risk neurosurgery.[15] In this scenario of high unmet medical need, the tolerance for a manageable side effect like reversible hepatotoxicity is substantially greater. The repurposing of Exisulind for FCCM strategically shifts the drug from a low-risk-tolerance setting to a high-risk-tolerance one, potentially creating a viable path to approval where one did not previously exist.

Recommendations for Future Research

The legacy of Exisulind confirms the therapeutic potential of targeting the cGMP-PKG signaling pathway for cancer and other diseases. Future research should build on these lessons. The development of next-generation SAANDs or selective PDE inhibitors should be prioritized, with a focus on designing molecules that retain the on-target efficacy of Exisulind but have been structurally modified to mitigate or eliminate the chemical liabilities responsible for hepatotoxicity.[29] Furthermore, clinical investigation of Exisulind itself for the treatment of FCCM is warranted to determine if its mechanistic promise can translate into a meaningful clinical benefit for this underserved patient population.

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