Xiong Yan, Li Fengling, Babault Nicolas, Wu Hong, Dong Aiping, Zeng Hong, Chen Xin, Arrowsmith Cheryl H, Brown Peter J, Liu Jing, Vedadi Masoud, Jin Jian
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
Bioorg Med Chem. 2017 Aug 15;25(16):4414-4423. doi: 10.1016/j.bmc.2017.06.021. Epub 2017 Jun 19.
Given the high homology between the protein lysine methyltransferases G9a-like protein (GLP) and G9a, it has been challenging to develop potent and selective inhibitors for either enzyme. Recently, we reported two quinazoline compounds, MS0124 and MS012, as GLP selective inhibitors. To further investigate the structure-activity relationships (SAR) of the quinazoline scaffold, we designed and synthesized a range of analogs bearing different 2-amino substitutions and evaluated their inhibition potencies against both GLP and G9a. These studies led to the identification of two new GLP selective inhibitors, 13 (MS3748) and 17 (MS3745), with 59- and 65-fold higher potency for GLP over G9a, which were confirmed by isothermal titration calorimetry (ITC). Crystal structures of GLP and G9a in complex with 13 and 17 provide insight into the interactions of the inhibitors with both proteins. In addition, we generated GLP selective inhibitors bearing a quinoline core instead of the quinazoline core.
鉴于蛋白质赖氨酸甲基转移酶G9a样蛋白（GLP）和G9a之间具有高度同源性，开发针对这两种酶的强效且选择性的抑制剂一直具有挑战性。最近，我们报道了两种喹唑啉化合物MS0124和MS012，作为GLP选择性抑制剂。为了进一步研究喹唑啉支架的构效关系（SAR），我们设计并合成了一系列带有不同2-氨基取代基的类似物，并评估了它们对GLP和G9a的抑制效力。这些研究导致鉴定出两种新的GLP选择性抑制剂13（MS3748）和17（MS3745），其对GLP的效力比对G9a高59倍和65倍，这通过等温滴定量热法（ITC）得到证实。GLP和G9a与13和17复合物的晶体结构揭示了抑制剂与这两种蛋白质的相互作用。此外，我们生成了带有喹啉核心而非喹唑啉核心的GLP选择性抑制剂。
