Design, synthesis, and structure-activity relationships of 1,2,3-triazole benzenesulfonamides as new selective leucine-zipper and sterile-alpha motif kinase (ZAK) inhibitors
Design, synthesis, and structure-activity relationships of 1,2,3-triazole benzenesulfonamides as new selective leucine-zipper and sterile-alpha motif kinase (ZAK) inhibitors
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作为新型选择性亮氨酸拉链和无菌 α 基序激酶 (ZAK) 抑制剂的 1,2,3-三唑苯磺酰胺的设计、合成和构效关系
DOI：
10.1021/acs.jmedchem.9b00664
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发表时间：
2020
影响因子：
7.3
通讯作者：
Xiaoyun Lu
中科院分区：
文献类型：
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作者：
Jianzhang Yang;Marth;am Asokan Shibu;Lulu Kong;Jinfeng Luo;Farheen BadrealamKhan;Yanhui Huang;Zheng-Chao Tu;Cai-Hong Yun;Chih-Yang Huang;Ke Ding;Xiaoyun Lu
ZAK是抗肥厚型心肌病（HCM）药物的一个新靶点。设计并合成了一系列1，2，3-三唑苯磺酰胺类ZAK选择性抑制剂。其中一种化合物6p与ZAK蛋白紧密结合（Kd= 8.0 nM），并以个位数nM（IC 50 = 4.0 nM）有效抑制ZAK的激酶功能，并在KINOMEscan筛选平台中对一组403种野生型激酶表现出优异的选择性。该化合物剂量依赖性地阻断p38/加塔-4和JNK/c-Jun信号传导，并在自发性高血压大鼠（SHR）模型中口服给药后显示出有希望的体内抗HCM功效。化合物6p可作为新的抗HCM药物发现的先导化合物。
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,6pbinds 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. Compound6pmay serve as a lead compound for new anti-HCM drug discovery.