title: Discovery of novel nonpeptide allosteric inhibitors interrupting the interaction of CDK2/cyclin A3 by virtual screening and bioassays.
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.
authors: 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.
authors: Yutong
authors: Y
authors: Hu
authors: 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.
authors: Shuai
authors: S
authors: Li
authors: Surgery Department of the Second Affiliated Hospital, Dalian Medical University, Dalian 116023, China.
authors: Fang
authors: F
authors: Liu
authors: 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.
authors: Lv
authors: L
authors: Geng
authors: College of Pharmacy, Dalian Medical University, Dalian 116044, China. Electronic address: xiaohong_shu@dlmedu.edu.cn.
authors: Xiaohong
authors: X
authors: Shu
authors: 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.
authors: Jian
authors: J
authors: Zhang
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D001681:Biological Assay; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019925:Cyclin A / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D019925:Cyclin A; D010455:Peptides; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: Allosteric regulation; CDK2 allosteric inhibitors; Cell cycle; Virtual screening