CDK9: A Comprehensive Review of Its Biology, and Its Role as a Potential Target for Anti-Cancer Agents

Abstract

Cyclin-dependent kinases (CDKs) are proteins pivotal to a wide range of cellular functions, most importantly cell division and transcription, and their dysregulations have been implicated as prominent drivers of tumorigenesis. Besides the well-established role of cell cycle CDKs in cancer, the involvement of transcriptional CDKs has been confirmed more recently. Most cancers overtly employ CDKs that serve as key regulators of transcription (e.g., CDK9) for a continuous production of short-lived gene products that maintain their survival. As such, dysregulation of the CDK9 pathway has been observed in various hematological and solid malignancies, making it a valuable anticancer target. This therapeutic potential has been utilized for the discovery of CDK9 inhibitors, some of which have entered human clinical trials. This review provides a comprehensive discussion on the structure and biology of CDK9, its role in solid and hematological cancers, and an updated review of the available inhibitors currently being investigated in preclinical and clinical settings.

CDK9 inhibitors in multiple myeloma: a review of progress and perspectives

“…Currently, all CDK9 inhibitors that have advanced to the second phase of clinical trials are non-selective, reversible and require continuous target occupancy to maintain CDK9 inhibition [ 15 , 94 ]. As those agents bind to the CDK9/cyclinT1 complex in an ATP-competitive manner, the CDK9 blockade may be prone to be overrun by residual CDK9 activity, limiting their clinical effectiveness [ 10 , 12 , 15 , 23 ].…”

“…Currently, all CDK9 inhibitors that have advanced to the second phase of clinical trials are non-selective, reversible and require continuous target occupancy to maintain CDK9 inhibition [ 15 , 94 ]. As those agents bind to the CDK9/cyclinT1 complex in an ATP-competitive manner, the CDK9 blockade may be prone to be overrun by residual CDK9 activity, limiting their clinical effectiveness [ 10 , 12 , 15 , 23 ]. Due to the lack of human clinical trials with selective CDK9 inhibitors and the off-target toxicity of the first generation CDK9 inhibitors, an alternative method to blocking the CDK9 activity was sought.…”

“…CDK9 is a member of the transcriptional cyclin-dependent kinases family which can be found in two isoforms CDK9 42 and CDK9 55 [ 15 ]. Together with cyclins T1, T2a, and T2b it forms a Positive Transcription Elongation Factor (P-TEFb).…”

“…Most of the cellular P-TEFb is inactive, sequestrated by the 7SK snRNA complex, but can be mobilized through BRD4 binding. Together, P-TEFb and BRD4 are capable of phosphorylating RNA pol II, sustaining transcription [ 15 , 16 ]. Although CDK9 42 and CDK9 55 share the ability to phosphorylate RNA pol II there seems to be some difference between their function.…”

“…CDK9 was shown to take part in c-MYC oncogene activation and Mcl-1 and Bcl-2 protein overexpression. Since those proteins were proved to have an important role in the progression of hematological malignancies, CDK9 inhibitors are currently widely researched in those diseases [ 15 ].…”