2. Academic Validation
  3. Discovery of Novel N-(5-(Pyridin-3-yl)-1 H-indazol-3-yl)benzamide Derivatives as Potent Cyclin-Dependent Kinase 7 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease

Discovery of Novel N-(5-(Pyridin-3-yl)-1 H-indazol-3-yl)benzamide Derivatives as Potent Cyclin-Dependent Kinase 7 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease

  • J Med Chem. 2022 Nov 17. doi: 10.1021/acs.jmedchem.2c01334.
Bowen Yang 1 2,  Haoran Zhang 3,  Na Li 2 4,  Lixin Gao 5,  Hong Jiang 1 2,  Weijuan Kan 5,  Haoxing Yuan 3,  Jia Li 5 4,  Dongmei Zhao 1,  Bing Xiong 2 4,  Yubo Zhou 5,  Dong Guo 3,  Tongchao Liu 2
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Lu, Shenyang 110016, P. R. China.
  • 2 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
  • 3 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No. 209, Tongshan Road, Yunlong District, Xuzhou, Jiangsu Province 221004, China.
  • 4 University of Chinese Academy of Sciences, NO. 19A Yuquan Road, Beijing 100049, P. R. China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
PMID: 36384292 DOI: 10.1021/acs.jmedchem.2c01334
Abstract

Recent evidence suggests that CDK7 is a novel potential drug target for autosomal dominant polycystic kidney disease (ADPKD) treatment. Herein, on the basis of structural analysis, a hit compound 3 with a novel scaffold was designed and subsequent medicinal chemistry efforts by a rational design strategy were conducted to improve CDK7 inhibitors' potency and selectivity. The representative compound B2 potently inhibited CDK7 with an IC50 value of 4 nM and showed high selectivity over CDKs. Compound B2 showed high potency to inhibit cyst growth and exhibited lower cytotoxicity than THZ1 in an in vitro Madin-Darby canine kidney cyst model. In addition, compound B2 was also highly efficacious in suppressing renal cyst development in an ex vivo embryonic kidney cyst model and in vivo ADPKD mouse model. These results indicate that compound B2 represents a promising lead compound that deserves further investigation to discover novel therapeutic agents for ADPKD.

Figures
Products