Summary
CDK4/6 inhibitors plus endocrine therapy is a standard therapy for HR+/HER2- breast cancer. Herein, using structure-based drug design strategy, a novel series of palbociclib derivatives were designed and synthesized as CDK4/6 inhibitors, among which compound 17m exhibited more potent CDK4/6 inhibitory activity and in vitro antiproliferative activity against the phosphorylated Rb-positive cell line MDA-MB-453 than the approved drug palbociclib. Moreover, compound 17m possessed remarkable CDK4/6 selectivity over other CDK family members including CDK1, CDK2, CDK3, CDK5, CDK7 and CDK9. The potent and selective CDK4/6 inhibitory activity endowed compound 17m with robust G1 cell cycle arrest ability in MDA-MB-453 cells. The intracellular inhibition of CDK4/6 by 17m was confirmed by western blot analysis of the levels of phosphorylated Rb in MDA-MB-453 cells. With respect to the metabolic stability, compound 17m possessed longer half-life (t1/2) in mouse liver microsome than palbociclib.
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This study was funded by grants from the National Natural Science Foundation of China (Grant No. 82073872).
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XX and LLN designed the project. LMZ and JW performed the enzymatic screening; LYX and CFQ synthesized the molecules; WYJ and LY performed the in vitro experiments. XX analyzed the data and wrote the manuscript.
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Li, L., Chen, F., Li, M. et al. Development of novel palbociclib-based CDK4/6 inhibitors exploring the back pocket behind the gatekeeper. Invest New Drugs 41, 638–651 (2023). https://doi.org/10.1007/s10637-023-01385-0
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DOI: https://doi.org/10.1007/s10637-023-01385-0