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

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.
Jianzhang Yang 1,  Marthandam Asokan Shibu 2,  Lulu Kong 3,  Jinfeng Luo 4,  Farheen BadrealamKhan 2,  Yanhui Huang 4,  Zheng-Chao Tu 4,  Cai-Hong Yun 3,  Chih-Yang Huang 2 5 6,  Ke Ding 1,  Xiaoyun Lu 1
Affiliations

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 (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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