IHMT-337

IHMT-337 is a **potent, highly selective, and irreversible inhibitor** of enhancer of zeste homolog 2 (**EZH2**), an enzymatic subunit of the Polycomb Repressive Complex 2 (PRC2). It works by **covalently binding to the EZH2 enzyme at the Cys663 residue in the SET domain**, thereby inhibiting EZH2's methyltransferase activity—specifically blocking methylation of histone H3 at lysine 27 (H3K27me3). Unlike other EZH2 inhibitors, IHMT-337 additionally induces **proteasome-mediated degradation of EZH2** via CHIP E3 ligase-mediated ubiquitination. This dual mechanism leads to inhibition of EZH2-mediated gene silencing and transcriptional repression. IHMT-337 also targets *CDK4* transcription, indicating a unique activity profile beyond classical enzymatic inhibition. Developed originally for malignancies such as **diffuse large B-cell lymphoma (DLBCL)** and **triple-negative breast cancer (TNBC)**, IHMT-337 has also shown efficacy in preclinical models of **glioma**, where it crosses the blood–brain barrier and suppresses tumor progression[1][2][5][7][10].