Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase

Journal Article · Tue Feb 14 04:00:00 EST 2017 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.6b01645· OSTI ID:1373766

Xiong, Yan; Li, Fengling; Babault, Nicolas; Dong, Aiping; Zeng, Hong; Wu, Hong; Chen, Xin; Arrowsmith, Cheryl H.; Brown, Peter J.; Liu, Jing; Vedadi, Masoud; Jin, Jian

G9a-like protein (GLP) and G9a are highly homologous protein lysine methyltransferases (PKMTs) sharing approximately 80% sequence identity in their catalytic domains. GLP and G9a form a heterodimer complex and catalyze mono- and dimethylation of histone H3 lysine 9 and nonhistone substrates. Although they are closely related, GLP and G9a possess distinct physiological and pathophysiological functions. Thus, GLP or G9a selective small-molecule inhibitors are useful tools to dissect their distinct biological functions. We previously reported potent and selective G9a/GLP dual inhibitors including UNC0638 and UNC0642. Here we report the discovery of potent and selective GLP inhibitors including 4 (MS0124) and 18 (MS012), which are >30-fold and 140-fold selective for GLP over G9a and other methyltransferases, respectively. The cocrystal structures of GLP and G9a in the complex with either 4 or 18 displayed virtually identical binding modes and interactions, highlighting the challenges in structure-based design of selective inhibitors for either enzyme.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: INDUSTRYNIH
• OSTI ID: 1373766
• Journal Information: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 5 Vol. 60; ISSN 0022-2623
• Publisher: American Chemical Society (ACS)
• Country of Publication: United States
• Language: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES