3 years ago

Structure Based Design of N-(3-((1H-Pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides as Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors

Structure Based Design of N-(3-((1H-Pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides as Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors
Cai-Hong Yun, Zhang Zhang, Peng Zhao, Yu Chang, Ke Ding, Yingjun Li, Zheng-Chao Tu, Chih-Yang Huang, Qing-Wen Zhang, Yong Xu, Jinfeng Luo, Yi-Bo Dai, Marthandam Asokan Shibu, Yan Zhang, Xiaoyun Lu
A series of N-(3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides were designed as the first class of highly selective ZAK inhibitors. The representative compound 3h strongly inhibits the kinase activity of ZAK with an IC50 of 3.3 nM and dose-dependently suppresses the activation of ZAK downstream signals in vitro and in vivo, while it is significantly less potent for the majority of 403 nonmutated kinases evaluated. Compound 3h also exhibits orally therapeutic effects on cardiac hypertrophy in a spontaneous hypertensive rat model.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00572

DOI: 10.1021/acs.jmedchem.7b00572

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