Discovery of novel macrocyclic derivatives as potent and selective cyclin-dependent kinase 2 inhibitors

Pengpeng Niu; Yanxin Tao; Qingyuan Meng; Yixing Huang; Shan Li; Ke Ding; Dawei Ma; Zu Ye; Mengyang Fan

doi:10.1016/j.bmc.2024.117711

Discovery of novel macrocyclic derivatives as potent and selective cyclin-dependent kinase 2 inhibitors

Bioorg Med Chem. 2024 Apr 15:104:117711. doi: 10.1016/j.bmc.2024.117711. Epub 2024 Apr 3.

Authors

Pengpeng Niu¹, Yanxin Tao², Qingyuan Meng³, Yixing Huang⁴, Shan Li⁵, Ke Ding⁶, Dawei Ma⁶, Zu Ye⁷, Mengyang Fan⁸

Affiliations

¹ Academy of Medical Engineering and Translational Medicine (AMT), Tianjin University, Tianjin 300072, China; Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China.
² School of Life Sciences, Tianjin University, Tianjin 300072, China; Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China.
³ Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China; Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
⁴ Department of Otorhinolaryngology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310022, China.
⁵ Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China.
⁶ Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 20032, China.
⁷ Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China. Electronic address: [email protected].
⁸ Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China. Electronic address: [email protected].

PMID: 38583237
DOI: 10.1016/j.bmc.2024.117711

Abstract

Cyclin-dependent kinase 2 (CDK2) is a member of CDK family of kinases (CDKs) that regulate the cell cycle. Its inopportune or over-activation leads to uncontrolled cell cycle progression and drives numerous types of cancers, especially ovarian, uterine, gastric cancer, as well as those associated with amplified CCNE1 gene. However, developing selective lead compound as CDK2 inhibitors remains challenging owing to similarities in the ATP pockets among different CDKs. Herein, we described the optimization of compound 1, a novel macrocyclic inhibitor targeting CDK2/5/7/9, aiming to discover more selective and metabolically stable lead compound as CDK2 inhibitor. Molecular dynamic (MD) simulations were performed for compound 1 and 9 to gain insights into the improved selectivity against CDK5. Further optimization efforts led to compound 22, exhibiting excellent CDK2 inhibitory activity, good selectivity over other CDKs and potent cellular effects. Based on these characterizations, we propose that compound 22 holds great promise as a potential lead candidate for drug development.

Keywords: CCNE1 amplification; Cyclin-dependent kinase 2; Macrocycle; Molecular dynamic simulations; Small molecule inhibitor.

MeSH terms

Cell Cycle
Cyclin-Dependent Kinase 2
Phosphorylation
Protein Kinase Inhibitors* / pharmacology

Substances

Cyclin-Dependent Kinase 2
Protein Kinase Inhibitors