Discovery of 3,6-disubstutited-imidazo[1,2-a]pyridine derivatives as a new class of CLK1 inhibitors

Yun Zhang; Anjie Xia; Shiyu Zhang; Guifeng Lin; Jingming Liu; Pei Chen; Bo Mu; Yan Jiao; Wenwen Xu; Mingxin Chen; Linli Li

doi:10.1016/j.bmcl.2021.127881

Discovery of 3,6-disubstutited-imidazo[1,2-a]pyridine derivatives as a new class of CLK1 inhibitors

Bioorg Med Chem Lett. 2021 Jun 1:41:127881. doi: 10.1016/j.bmcl.2021.127881. Epub 2021 Mar 2.

Authors

Yun Zhang¹, Anjie Xia², Shiyu Zhang³, Guifeng Lin², Jingming Liu², Pei Chen³, Bo Mu⁴, Yan Jiao², Wenwen Xu³, Mingxin Chen², Linli Li⁵

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Macular Disease Research Laboratory, Department of Ophthalmology, West China Hospital, Sichuan University, Sichuan 610041, China.
² State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
³ Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China.
⁴ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Basic Medical College of North Sichuan Medical College, Nanchong 637000, Sichuan, China.
⁵ Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China. Electronic address: lilinli@scu.edu.cn.

PMID: 33662541
DOI: 10.1016/j.bmcl.2021.127881

Abstract

Inhibition of cdc2-like kinase1 (CLK1) could efficiently induce autophagy and it has been thought as a potential target for treatment of autophagy-related diseases. Herein we report the discovery of a series of 3,6-disubstutited-imidazo[1,2-a]pyridine derivatives as a new class of CLK1 inhibitors. Among them, compound 9e is the most potent one, which exhibits an IC₅₀ value of 4 nM against CLK1 kinase. In vitro, this compound reduces the phosphorylation level of the typical downstream substrates of CLK1 and affects their subcellular redistribution. Further study indicates that 9e is efficient to induce autophagy. Overall, this study provides a promising lead compound for drug discovery targeting CLK1 kinase.

Keywords: Autophagy; CLK1; Small molecule inhibitor; Structure-activity relationship.

Publication types

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

MeSH terms

Binding Sites
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Structure
Protein Binding
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / antagonists & inhibitors*

Substances

Enzyme Inhibitors
Clk dual-specificity kinases
Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases