Structure-guided design and development of cyclin-dependent kinase 4/6 inhibitors: A review on therapeutic implications

Cyclin-dependent kinase 6 (EC 2.7.11.22) play significant roles in numerous biological processes and triggers cell cycle events. CDK6 controlled the transcriptional regulation. A dysregulated function of CDK6 is linked with the development of progression of multiple tumor types. Thus, it is considered as an effective drug target for cancer therapy. Based on the direct roles of CDK4/6 in tumor development, numerous inhibitors developed as promising anti-cancer agents. CDK4/6 inhibitors regulate the G1 to S transition by preventing Rb phosphorylation and E2F liberation, showing potent anti-cancer activity in several tumors, including HR+/HER2-breast cancer. CDK4/6 inhibitors such as abemaciclib, palbociclib, and ribociclib, control cell cycle, provoke cell senescence, and in-duces tumor cell disturbance in pre-clinical studies. Here, we discuss the roles of CDK6 in cancer along with the present status of CDK4/6 inhibitors in cancer therapy. We further discussed, how structural features of CDK4/6 could be implicated in the design and development of potential anti-cancer agents. In addition, the therapeutic potential and limitations of available CDK4/6 inhibitors are described in detail. Recent pre-clinical and clinical information for CDK4/6 inhibitors are highlighted. In addition, combination of CDK4/6 inhibitors with other drugs for the therapeutic management of cancer are discussed.

Automated summary

Cyclin-dependent kinase 6 (CDK6) plays a significant role in cancer and is considered an effective drug target for therapy. CDK4/6 inhibitors have shown promising anti-cancer activity by preventing tumor development through inhibiting Rb phosphorylation and E2F liberation. This article discusses the roles of CDK6 in cancer, the current status of CDK4/6 inhibitors in therapy, and emphasizes the potential of combining CDK4/6 inhibitors with other drugs for cancer treatment.