The novel selective inhibitors of cyclin-dependent kinase 4/6: in vitro and in silico study

One of the main regulators in the cell cycle is cyclin-dependent kinase 4 and 6 (CDK4/6). FDA has approved CDK4/6 inhibitors for the treatment of patients with metastatic breast cancer. However, the development of selective agents remains problematic due to the conservation of their ATP binding sites. In the previous in silico study, ZINC585292724, ZINC585292587, ZINC585291674, and ZINC585291474 have been identified as potential inhibitors. Therefore, the present study aimed to analyze the selectivity and inhibitory activity of the four compounds against CDK4/6 in vitro as well as determine the potential for their further development in silico. The in vitro results showed that the four compounds had good selectivity towards both kinases, due to their similar structure. In agreement with the in silico results, ZINC585291674 produced the best inhibitory activity against CDK4 and CDK6, with IC50 of 184.14 nM and 111.78 nM, respectively. Their ADMET profile were also similar to reference compound of Palbociclib. Based on this, ZINC585291674 can be used as a lead compound for further inhibitor development.