RESUMO
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.
RESUMO
The Cyclin-Dependent Kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. These kinases are closely related to oncogenesis and have been proved to be attractive targets for designing novel anticancer agents. The CDK inhibitors can effectively suppress the excessive proliferation of tumor cells by inducing cell cycle arrest. In recent years, a large number of CDK inhibitors have entered pre-clinical and/or clinical trials. Among these compounds, the selective CDK4/6 inhibitor Palbociclib has been approved by FDA for breast cancer treatment. Moreover, Palbociclib demonstrated promising antitumor potential as monotherapy or combined therapy in numerous clinical trials. Herein, we provide a brief review focused on the recent progress of clinical studies about Palbociclib.