The histone methyltransferase EZH2 is the catalytic subunit of the PRC2 complex and catalyzes the methylation of histone H3 on lysine 27 (H3K27) resulting in transcriptional suppression. EZH2 is frequently mutated in B-cell lymphomas and is mutated or overexpressed in a number of solid tumors, where its expression level often correlates with poor prognosis. Cancers usurp EZH2 catalytic function to silence expression of tumor suppressors and pro-apoptotic genes. Preclinical studies show that sustained EZH2 inhibition is required to reverse these effects, triggering tumor growth inhibition. First generation EZH2 inhibitors are currently being used in the clinic and have shown clinical benefit in lymphomas and other indications. Continued efforts to optimize EZH2 small molecule inhibitors resulted in identification of the 4-thiomethyl pyridone as a key modification that led to a significant increase in potency and prolonged residence time. Leveraging this finding, we have optimized a series of EZH2 inhibitors with enhanced anti-tumor activity and improved physiochemical properties which have the potential to expand the clinical use of EZH2 inhibitors.

Discovery of thiomethyl pyridones: Design, synthesis and pharmacological evaluation of second generation EZH2 inhibitors with long residence times

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.