SAH derived potent and selective EZH2 inhibitors

Bioorganic & Medicinal Chemistry Letters
Pei-Pei KungKaren A Maegley

Abstract

A series of novel enhancer of zeste homolog 2 (EZH2) inhibitors was designed based on the chemical structure of the histone methyltransferase (HMT) inhibitor SAH (S-adenosyl-l-homocysteine). These nucleoside-based EZH2 inhibitors blocked the methylation of nucleosomes at H3K27 in biochemical assays employing both WT PRC2 complex as well as a Y641N mutant PRC2 complex. The most potent compound, 27, displayed IC50's against both complexes of 270 nM and 70 nM, respectively. To our knowledge, compound 27 is the most potent SAH-derived inhibitor of the EZH2 PRC2 complex yet identified. This compound also displayed improved potency, lipophilic efficiency (LipE), and selectivity profile against other lysine methyltransferases compared with SAH.

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Citations

Mar 18, 2016·ACS Medicinal Chemistry Letters·Cen GaoMary M Mader
Nov 19, 2015·International Journal of Molecular Sciences·Mónica Martínez-FernándezJesús M Paramio
Aug 23, 2016·Future Medicinal Chemistry·Uttara Soumyanarayanan, Brian W Dymock
Aug 30, 2016·ACS Chemical Biology·Dominic TisiTom D Heightman
Jun 20, 2020·ACS Medicinal Chemistry Letters·Ting-Rong ChernShaomeng Wang
Dec 8, 2020·Journal of Medicinal Chemistry·M Cynthia MartinGary E Schiltz

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