Small Molecule Inhibitors of Cyclin-Dependent Kinase 9 for Cancer Therapy: A Review

This chapter reviews recent Cyclin-dependent kinase 9 (CDK9) patent literature (2012–2020) pertaining to the management of cancer with small molecule inhibitors, including their selectivity profile and biological outcomes in preclinical investigations. By controlling the short-lived anti-apoptotic genes necessary for cancer cell survival, CDK9 is an essential transcription factor. Consequently, one possible cancer treatment option is to use small molecule inhibitors to target CDK9. A number of CDK9 inhibitors have been evaluated in clinical trials mainly as ATP competitive inhibitors for the treatment of various types of cancers. The first generation of CDK9 inhibitors that reached the clinical trials were pan-CDK inhibitors, which inhibited CDK9 as well as other CDK isoforms and other kinases. Examples of these CDK9 inhibitors are flavopiridol, dinaciclib, SNS-032, and zotiraciclib. The clinical results with these inhibitors showed good responses, but they also showed a high incidence of adverse effects. The new generation of CDK9 inhibitors selectively inhibited CDK9 over other CDK isoforms and other kinases. Currently, there are three highly selective CDK9 inhibitors in clinical evaluation targeting hematological malignancies: atuveciclib, BAY-1251152, and AZD4573. The main chemical scaffolds of clinical and patent CDK9 inhibitors were focused on 2-aminopyridine/pyrimidines, 2-aminotriazines, and pyrrolo[2,3-b]pyridines.