Prelude Therapeutics Unveils Novel JAK2V617F-Selective Inhibitor and mCALR-Targeted Therapy for Myeloproliferative Neoplasms
核心洞察
Prelude Therapeutics presented first preclinical data for PRT12396 (搜索), a JAK2V617F (搜索)-selective JH2 inhibitor that demonstrates disease-modifying potential in myeloproliferative neoplasms (搜索) while preserving normal JAK2 (搜索) function.
The company also disclosed a novel mutant calreticulin (mCALR (搜索)) targeted degrader antibody conjugate with a CDK9 (搜索) degrader payload that selectively kills malignant clones while sparing healthy cells.
PRT12396 (搜索) has completed GLP toxicology studies and is on track for IND filing in the first quarter of 2026, with the program subject to an exclusive option agreement with Incyte.
Prelude Therapeutics presented groundbreaking preclinical data at the American Society of Hematology (ASH) 67th Annual Meeting, unveiling two innovative therapeutic approaches for myeloproliferative neoplasms (搜索) (MPNs) that target the disease's primary driver mutations. The precision oncology company disclosed first-in-class data on PRT12396 (搜索), a JAK2V617F (搜索)-selective JH2 inhibitor, and a novel mutant calreticulin (mCALR (搜索)) targeted degrader antibody conjugate.
JAK2V617F-Selective Inhibitor Shows Promise
PRT12396 (搜索) represents a significant advancement in addressing a decades-old challenge in MPN treatment. "Since JAK2V617F (搜索) was first identified as a major driver mutation in JAK2 (搜索) enzyme in myeloproliferative neoplasms (搜索) two decades ago, our industry has been searching for an inhibitor that can selectively target the mutant JAK2 enzyme without disrupting normal JAK2 function," stated Kris Vaddi, Ph.D., Chief Executive Officer of Prelude.
The JAK2V617F (搜索) mutation affects approximately 95% of patients with polycythemia vera (搜索) (PV), 60% of patients with essential thrombocythemia (搜索) (ET), and 55% of patients with myelofibrosis (搜索) (MF). Prelude's novel allosteric inhibitors bind into the JAK2 (搜索) JH2 "deep pocket" where the V617F mutation resides, demonstrating mutant-specific inhibition in multiple preclinical models of MPNs.
Preclinical studies showed that PRT12396 (搜索) selectively inhibits JAK2V617F (搜索) activity in a cellular context while preserving wild-type JAK2 (搜索)-mediated cytokine signaling. The compound demonstrated robust preclinical activity in multiple MPN models, showing superiority to ruxolitinib. Additionally, PRT12396 showed selective inhibition of the proliferation of JAK2VF stem and progenitor cells both in vitro and in vivo and was well-tolerated in toxicological studies with minimal effects on hematologic parameters.
Clinical Development Timeline
The company has completed GLP toxicology studies and anticipates filing the IND and initiating a phase 1 study in the first quarter of 2026. The JAK2V617F (搜索) inhibitor program is subject to an exclusive option agreement with Incyte announced in November 2025.
mCALR-Targeted Degrader Antibody Conjugate
Prelude also presented data from its mutant calreticulin (mCALR (搜索)) degrader antibody conjugates (DACs) discovery program. Mutant CALR is a neoantigen presented on the cell surface of malignant myeloid cells but not normal cells and is found in approximately 25-35% of patients with MF and ET.
The mCALR (搜索) x CDK9 (搜索) degrader antibody conjugate delivers a CDK9 degrader selectively to malignant clones. The approach demonstrated deep mutant-selective killing across cell lines, HSPCs and primary cultures, highlighting disease-modifying potential supported by compelling in vivo efficacy data. The mCALR x CDK9 DACs were shown to spare healthy hematopoietic cells, indicating potential for a favorable therapeutic index.
"Our degrader antibody conjugate (DAC) approach is designed to build on this validation by delivering a disease-relevant payload, such as our highly potent CDK9 (搜索) degrader, directly to mCALR (搜索)-positive cells," explained Vaddi. "We believe this innovative strategy offers a differentiated, and potentially even more efficacious approach as we seek to advance the next wave of disease-modifying therapies for MPN patients."
Therapeutic Potential
Both therapeutic approaches target JAK2V617F (搜索) and mCALR (搜索), the two primary driver mutations responsible for disease progression and poor prognosis in the majority of MPN patients. Prelude believes these approaches may have the potential to reduce mutant allele burden, slow or even reverse disease progression, and transform treatment outcomes for MPN patients.
The company's work represents a significant step forward in precision oncology for MPNs, addressing long-standing challenges in developing therapies that can selectively target malignant cells while preserving normal cellular function. The disease-modifying potential demonstrated in preclinical studies suggests these approaches could offer meaningful advances beyond current JAK2 (搜索) inhibitors.