BackMevrometostat
EZH2 Inhibitor
Mevrometostat is an investigational compound. Its safety and efficacy have not been established.
Overview + Rationale
As catalytic subunit of the polycomb repressive complex 2 (PRC2), enhancer of zeste homolog 2 (EZH2) plays a key role in epigenetic regulation, modifying gene expression patterns that control cell fate decisions, such as differentiation and self-renewal
EZH2 dysregulation in cancer occurs through activating mutations in lymphoma and over-expression in epithelial cancers:
• EZH2 is highly expressed in small-cell lung cancer, and was shown to contribute to pathogenesis and resistance to chemotherapy through changes in expression of genes involved in DNA repair
• In prostate cancer, EZH2 expression is associated with worse prognosis and plays a role in androgen-resistant disease
Mechanism of Action
- Mevrometostat is a highly specific orally bioavailable EZH2 inhibitor with Ki of <100 pM against both WT and mutant Y641N EZH2, respectively
- In pre-clinical studies, Mevrometostat has been shown to inhibit the catalytic activity of EZH2, which, combined with active demethylation by H3K27 histone demethylases UTX and JMJD3 and passive demethylation due to cell doubling, results in decrease in H3K27 methylation
- Loss of H3K27me3 results in reactivation of gene expression of EZH2 target genes
Stage of Development
