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

Yu Chang; Xiaoyun Lu; Marthandam Asokan Shibu; Yi-Bo Dai; Jinfeng Luo; Yan Zhang; Yingjun Li; Peng Zhao; Zhang Zhang; Yong Xu; Zheng-Chao Tu; Qing-Wen Zhang; Cai-Hong Yun; Chih-Yang Huang; Ke Ding

doi:10.1021/acs.jmedchem.7b00572

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

J Med Chem. 2017 Jul 13;60(13):5927-5932. doi: 10.1021/acs.jmedchem.7b00572. Epub 2017 Jun 16.

Authors

Yu Chang^{1

2}, Xiaoyun Lu², Marthandam Asokan Shibu^{3

4}, Yi-Bo Dai⁵, Jinfeng Luo⁶, Yan Zhang⁶, Yingjun Li⁶, Peng Zhao⁵, Zhang Zhang⁶, Yong Xu⁶, Zheng-Chao Tu⁶, Qing-Wen Zhang¹, Cai-Hong Yun⁵, Chih-Yang Huang^{3

4}, Ke Ding²

Affiliations

¹ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macao, China.
² School of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
³ Graduate Institute of Basic Medical Science, China Medical University , Taichung 404, Taiwan, China.
⁴ Department of Health and Nutrition Biotechnology, Asia University , Taichung 433, Taiwan, China.
⁵ Institute of Systems Biomedicine, Department of Biophysics and Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center , Beijing 100191, China.
⁶ Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.

PMID: 28586211
DOI: 10.1021/acs.jmedchem.7b00572

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.

MeSH terms

Animals
Benzenesulfonamides
Cardiomegaly / drug therapy
Cardiomegaly / metabolism
Drug Design
Humans
MAP Kinase Kinase Kinases
Molecular Docking Simulation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
Protein Kinases / metabolism*
Rats, Inbred SHR
Rats, Inbred WKY
Sulfonamides / chemistry*
Sulfonamides / pharmacology*
Sulfonamides / therapeutic use

Substances

Protein Kinase Inhibitors
Sulfonamides
Protein Kinases
MAP Kinase Kinase Kinases
MAP3K20 protein, human