2. Academic Validation
  3. Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase

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

  • J Med Chem. 2017 Mar 9;60(5):1876-1891. doi: 10.1021/acs.jmedchem.6b01645.
Yan Xiong 1,  Fengling Li 2,  Nicolas Babault 1,  Aiping Dong 2,  Hong Zeng 2,  Hong Wu 2,  Xin Chen 1,  Cheryl H Arrowsmith 2 3,  Peter J Brown 2,  Jing Liu 1,  Masoud Vedadi 2 4,  Jian Jin 1
Affiliations

Affiliations

  • 1 Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
  • 2 Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
  • 3 Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto , Toronto, Ontario M5G 2M9, Canada.
  • 4 Department of Pharmacology and Toxicology, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
PMID: 28135087 DOI: 10.1021/acs.jmedchem.6b01645
Abstract

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.

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