Design, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors

Jianzhang Yang; Marthandam Asokan Shibu; Lulu Kong; Jinfeng Luo; Farheen BadrealamKhan; Yanhui Huang; Zheng-Chao Tu; Cai-Hong Yun; Chih-Yang Huang; Ke Ding; Xiaoyun Lu

doi:10.1021/acs.jmedchem.9b00664

Design, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors

J Med Chem. 2020 Mar 12;63(5):2114-2130. doi: 10.1021/acs.jmedchem.9b00664. Epub 2019 Jun 17.

Authors

Jianzhang Yang¹, Marthandam Asokan Shibu², Lulu Kong³, Jinfeng Luo⁴, Farheen BadrealamKhan², Yanhui Huang⁴, Zheng-Chao Tu⁴, Cai-Hong Yun³, Chih-Yang Huang^{2

5

6}, Ke Ding¹, Xiaoyun Lu¹

Affiliations

¹ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
² Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan.
³ Department of Biochemistry and Biophysics, Institute of Systems Biomedicine and Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
⁴ Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China.
⁵ Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan.
⁶ College of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan.

PMID: 31244114
DOI: 10.1021/acs.jmedchem.9b00664

Abstract

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 (K_d = 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzenesulfonamides
Drug Design*
Humans
Leucine Zippers / drug effects
MAP Kinase Kinase Kinases / antagonists & inhibitors*
MAP Kinase Kinase Kinases / chemistry
MAP Kinase Kinase Kinases / metabolism
Molecular Docking Simulation
Protein Kinase Inhibitors / blood
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Rats
Rats, Inbred SHR
Rats, Inbred WKY
Structure-Activity Relationship
Sulfonamides / blood
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*
Triazoles / blood
Triazoles / chemical synthesis
Triazoles / chemistry
Triazoles / pharmacology*

Substances

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