Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update

Abstract

Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal transcriptional regulation that is frequently dysregulated in cancers. Emerging evidence indicates that selective CDK9 inhibition or degradation may provide a therapeutic benefit against certain cancers. Indeed, the development of CDK9 modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides an overview of recent advances in CDK9 modulators in general, with special emphasis on compounds under clinical evaluation and new emerging strategies, such as proteolysis targeting chimeras (PROTACs).