Discovery of novel nonpeptide allosteric inhibitors interrupting the interaction of CDK2/cyclin A3 by virtual screening and bioassays

Yutong Hu; Shuai Li; Fang Liu; Lv Geng; Xiaohong Shu; Jian Zhang

doi:10.1016/j.bmcl.2015.08.050

Discovery of novel nonpeptide allosteric inhibitors interrupting the interaction of CDK2/cyclin A3 by virtual screening and bioassays

Bioorg Med Chem Lett. 2015 Oct 1;25(19):4069-73. doi: 10.1016/j.bmcl.2015.08.050. Epub 2015 Aug 20.

Authors

Yutong Hu¹, Shuai Li², Fang Liu³, Lv Geng², Xiaohong Shu⁴, Jian Zhang⁵

Affiliations

¹ College of Pharmacy, Dalian Medical University, Dalian 116044, China; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
² Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
³ Surgery Department of the Second Affiliated Hospital, Dalian Medical University, Dalian 116023, China.
⁴ College of Pharmacy, Dalian Medical University, Dalian 116044, China. Electronic address: xiaohong_shu@dlmedu.edu.cn.
⁵ Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China. Electronic address: jian.zhang@sjtu.edu.cn.

PMID: 26316466
DOI: 10.1016/j.bmcl.2015.08.050

Abstract

Serine/threonine-specific cyclin-dependent kinases (CDKs) are key regulatory elements in eukaryotic cell cycle progression, and the dysregulation of CDKs has been implicated in cancers. Therefore, CDKs have been identified as anti-cancer targets for the development of small-molecule drugs. In this Letter, virtual screening and biological evaluation were performed to identify novel lead structures that allosterically disrupt the interaction between CDK2 and cyclin A3, which are directed toward a noncatalytic binding pocket of CDK2. Ultimately, B2 was identified as exhibiting superior CDK2/cyclin A3 inhibition activity. In addition, our results indicated that B2 exhibited antiproliferative activities against a broad spectrum of human cancer cell lines. Significantly, B2 certainly interrupted the interaction between CDK2 and cyclin A3 and exhibited a concentration-dependent trend. In summary, our results suggest that B2 is the first effective allosteric chemical small-molecule CDK2 inhibitor to be discovered, and further lead optimization may result in a series of novel anti-CDK2 agents.

Keywords: Allosteric regulation; CDK2 allosteric inhibitors; Cell cycle; Virtual screening.

Publication types

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

MeSH terms

Allosteric Regulation / drug effects
Biological Assay*
Cell Line, Tumor
Cell Survival / drug effects
Cyclin A / metabolism*
Cyclin-Dependent Kinase 2 / metabolism*
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical*
Humans
Molecular Dynamics Simulation
Molecular Structure
Peptides / chemistry*
Peptides / pharmacology*
Protein Binding / drug effects
Structure-Activity Relationship

Substances

Cyclin A
Peptides
CDK2 protein, human
Cyclin-Dependent Kinase 2