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
Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
J Med Chem. 2017 Mar 9;60(5):1876-1891. doi: 10.1021/acs.jmedchem.6b01645. Epub 2017 Feb 14.
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.
G9a样蛋白（GLP）和G9a是高度同源的蛋白质赖氨酸甲基转移酶（PKMT），其催化结构域的序列同一性约为80%。GLP和G9a形成异二聚体复合物，并催化组蛋白H3赖氨酸9和非组蛋白底物的单甲基化和二甲基化。尽管它们密切相关，但GLP和G9a具有不同的生理和病理生理功能。因此，GLP或G9a选择性小分子抑制剂是剖析其不同生物学功能的有用工具。我们之前报道了包括UNC0638和UNC0642在内的强效和选择性G9a/GLP双重抑制剂。在此，我们报告了强效和选择性GLP抑制剂的发现，包括4（MS0124）和18（MS012），它们对GLP的选择性分别比对G9a和其他甲基转移酶高30倍和140倍。GLP和G9a与4或18形成复合物的共晶体结构显示出几乎相同的结合模式和相互作用，突出了基于结构设计针对这两种酶的选择性抑制剂的挑战。
