AUTHOR=Liang Hanzhi , Zhu Yue , Zhao Zhiyuan , Du Jintong , Yang Xinying , Fang Hao , Hou Xuben 

TITLE=Structure-Based Design of 2-Aminopurine Derivatives as CDK2 Inhibitors for Triple-Negative Breast Cancer

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.864342

DOI=10.3389/fphar.2022.864342

ISSN=1663-9812

ABSTRACT=<p>Cyclin-dependent kinase 2 (CDK2) regulates the progression of the cell cycle and is critically associated with tumor growth. Selective CDK2 inhibition provides a potential therapeutic benefit against certain tumors. Purines and related heterocycle (e.g., <italic>R</italic>-Roscovitine) are important scaffolds in the development of CDK inhibitors. Herein, we designed a new series of 2-aminopurine derivatives based on the fragment-centric pocket mapping analysis of CDK2 crystal structure. Our results indicated that the introduction of polar substitution at the C-6 position of purine would be beneficial for CDK2 inhibition. Among them, compound <bold>11l</bold> showed good CDK2 inhibitory activity (IC<sub>50</sub> = 19 nM) and possessed good selectivity against other CDKs. Further <italic>in vitro</italic> tests indicated that compound <bold>11l</bold> possesses anti-proliferation activity in triple-negative breast cancer (TNBC) cells. Moreover, molecular dynamics simulation suggested the favorable binding mode of compound <bold>11l</bold>, which may serve as a new lead compound for the future development of CDK2 selective inhibitors.</p>