Pelabresib
chemical compound
Pelabresib (CPI-0610; PELA) is an investigational oral small-molecule drug designed to inhibit bromodomain and extra-terminal domain (BET)-mediated gene transcription involved in the pathogenesis of myelofibrosis (MF) and other myeloproliferative neoplasms. Developed by Constellation Pharmaceuticals, a Novartis company, pelabresib targets epigenetic pathways to modulate oncogenic and inflammatory gene expression, offering a novel therapeutic approach for MF patients with limited treatment options.
As of May 2025, pelabresib is in Phase III clinical trials for MF and has shown promising results in combination with ruxolitinib, a Janus kinase inhibitor (JAKi), but is not yet approved for clinical use.
Mechanism of action
Pelabresib is a selective inhibitor of BET proteins (BRD2, BRD3, BRD4, BRDT), which regulate gene expression by binding to acetylated histones. In MF, BET proteins drive the expression of genes involved in nuclear factor kappa B (NF-κB) signaling, proinflammatory cytokine production (e.g., IL-6, TNF-α), and aberrant megakaryopoiesis, contributing to bone marrow fibrosis, splenomegaly, and systemic symptoms. By inhibiting BET proteins, pelabresib downregulates these pathogenic pathways, reducing cytokine levels, improving bone marrow function, and alleviating symptoms. Preclinical studies demonstrated synergistic effects when combined with JAKi like ruxolitinib, enhancing suppression of oncogenic and inflammatory signaling.
Preclinical studies
Preclinical studies established pelabresib’s efficacy in MF models. In JAK2V617F-mutant mouse models, pelabresib reduced spleen weight by 30–40% and decreased bone marrow fibrosis compared to controls, with significant reductions in IL-6 and TNF-α levels. Combination with ruxolitinib further decreased spleen size (up to 60%) and normalized megakaryocyte morphology.
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