861306-97-0Relevant academic research and scientific papers
Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase
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
, p. 1876 - 1891 (2017/03/17)
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.
Structure-activity relationship studies of SETD8 inhibitors
Ma, Anqi,Yu, Wenyu,Xiong, Yan,Butler, Kyle V.,Brown, Peter J.,Jin, Jian
, p. 1892 - 1898 (2015/01/08)
SETD8 (also known as SET8, PR-SET7, or KMT5A (lysine methyltransferase 5A)) is the only known lysine methyltransferase that catalyzes the monomethylation of histone H4 lysine 20 (H4K20). In addition to H4K20, SETD8 monomethylates non-histone substrates such as the tumor suppressor p53 and the proliferating cell nuclear antigen (PCNA). Because of its role in regulating diverse biological processes, SETD8 has been pursued as a potential therapeutic target. We recently reported the first substrate-competitive SETD8 inhibitor, UNC0379 (1), which is selective for SETD8 over 15 other methyltransferases. We characterized this inhibitor in a battery of biochemical and biophysical assays. Here we describe our comprehensive structure-activity relationship (SAR) studies of this chemical series. In addition to 2- and 4-substituents, we extensively explored 6- and 7-substituents of the quinazoline scaffold. These SAR studies led to the discovery of several new compounds, which displayed similar potencies as compound 1 and interesting SAR trends. This journal is
Synthesis and biological evaluation of substituted 1,2,3-benzotriazines and pyrido[3,2-d]-1,2,3-triazines as inhibitors of vascular endothelial growth factor receptor-2
Zhao, Xing-Wang,Liu, Dan,Luan, Sheng-Lin,Hu, Guo-Dong,Lv, Jin-Ling,Jing, Yong-Kui,Zhao, Lin-Xiang
, p. 7807 - 7815 (2014/01/06)
A novel series of substituted 1,2,3-benzotriazines and pyrido[3,2-d]-1,2,3- triazines were synthesized. The abilities of these compounds to inhibit the VEGFR-2 kinase activity and the proliferation of human microvascular endothelial cells (MVECs) were det
Design, synthesis, and antitumor activities of some novel substituted 1,2,3-benzotriazines
Lv, Jin-Ling,Wang, Rui,Liu, Dan,Guo, Gang,Jing, Yong-Kui,Zhao, Lin-Xiang
, p. 1427 - 1440 (2008/12/20)
A series of novel substituted 1,2,3-benzotriazines based on the structures of vatalanib succinate (PTK787) and vandetanib (ZD6474) were designed and synthesized. The antiproliferative effects of these compounds were tested on microvascular endothelial cel
