Structure Based Design of <i>N</i>-(3-((1<i>H</i>-Pyrazolo[3,4-<i>b</i>]pyridin-5-yl)ethynyl)benzenesulfonamides as Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors
Yu Chang(Jinan University), Xiaoyun Lu(Jinan University), Marthandam Asokan Shibu(Asia University), Yi-Bo Dai(Peking University), Jinfeng Luo(Chinese Academy of Sciences), Yan Zhang(Chinese Academy of Sciences), Yingjun Li(Chinese Academy of Sciences), Peng Zhao(Peking University), Zhang Zhang(Chinese Academy of Sciences), Yong Xu(Chinese Academy of Sciences), Zheng-Chao Tu(Chinese Academy of Sciences), Qingwen Zhang(University of Macau), Cai-Hong Yun(Peking University), Chih‐Yang Huang(Asia University), Ke Ding(Jinan University)
Cited by 26Open Access
Abstract
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.
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