化学
铅化合物
激酶
结构-活动关系
药物发现
IC50型
体内
三唑
亮氨酸拉链
药理学
蛋白激酶A
体外
生物化学
生物
转录因子
遗传学
有机化学
基因
作者
Jianzhang Yang,Marthandam Asokan Shibu,Lulu Kong,Jinfeng Luo,Khan Farheen Badrealam,Yanhui Huang,Zhengchao Tu,Cai‐Hong Yun,Chih‐Yang Huang,Ke Ding,Xiaoyun Lu
标识
DOI:10.1021/acs.jmedchem.9b00664
摘要
ZAK is a new promising target for discovery of drugs with activity against antihypertrophic cardiomyopathy (HCM). A series of 1,2,3-triazole benzenesulfonamides were designed and synthesized as selective ZAK inhibitors. One of these compounds, 6p binds tightly to ZAK protein (Kd = 8.0 nM) and potently suppresses the kinase function of ZAK with single-digit nM (IC50 = 4.0 nM) and exhibits excellent selectivity in a KINOMEscan screening platform against a panel of 403 wild-type kinases. This compound dose dependently blocks p38/GATA-4 and JNK/c-Jun signaling and demonstrates promising in vivo anti-HCM efficacy upon oral administration in a spontaneous hypertensive rat (SHR) model. Compound 6p may serve as a lead compound for new anti-HCM drug discovery.
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