molecules of the month


oral, allosteric PRC2 inhibitor (EED)

in Ph. I/II for cancer (DLBCL); preliminary efficacy

from micromolar HTS hit

J. Med. Chem.

Novartis, Emeryville, CA

oral, allosteric PRC2 inhibitor (EED) - Novartis, Emeryville, CA
4 mins read

Context. MAK683 is an oral, allosteric and selective PRC2 inhibitor intended for PRC2-dependent cancers. PRC2 is an essential epigenetic regulator of gene expression and enhanced or diminished PRC2 function have been implicated in a number of cancers. Enhancer of zeste homolog 2 (EZH2), one of the four core components of PRC2 that directly trimethylates K27 of histone 3 (H3K27me3), has been the most extensively studied PRC2 subunit and a number of EZH2 mutations and post-translational modifications have reportedly been associated with disease progression. In addition, the approval of the first EZH2 inhibitor, Epizyme’s tazemetostat, for advanced/metastatic epithelioid sarcoma and relapsed/refractory follicular lymphoma further validated EZH2 and other PRC2 components as viable drug targets. Resistance mechanisms to EZH2 inhibitors have been…

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