Targeting CDK9 for Anti-Cancer Therapeutics

Abstract

Cyclin Dependent Kinase 9 (CDK9) is one of the most important transcription regulatory members of the CDK family. In conjunction with its main cyclin partner—Cyclin T1, it forms the Positive Transcription Elongation Factor b (P-TEFb) whose primary function in eukaryotic cells is to mediate the positive transcription elongation of nascent mRNA strands, by phosphorylating the S2 residues of the YSPTSPS tandem repeats at the C-terminus domain (CTD) of RNA Polymerase II (RNAP II). To aid in this process, P-TEFb also simultaneously phosphorylates and inactivates a number of negative transcription regulators like 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) Sensitivity-Inducing Factor (DSIF) and Negative Elongation Factor (NELF). Significantly enhanced activity of CDK9 is observed in multiple cancer types, which is universally associated with significantly shortened Overall Survival (OS) of the patients. In these cancer types, CDK9 regulates a plethora of cellular functions including proliferation, survival, cell cycle regulation, DNA damage repair and metastasis. Due to the extremely critical role of CDK9 in cancer cells, inhibiting its functions has been the subject of intense research, resulting the development of multiple, increasingly specific small-molecule inhibitors, some of which are presently in clinical trials. The search for newer generation CDK9 inhibitors with higher specificity and lower potential toxicities and suitable combination therapies continues. In fact, the Phase I clinical trials of the latest, highly specific CDK9 inhibitor BAY1251152, against different solid tumors have shown good anti-tumor and on-target activities and pharmacokinetics, combined with manageable safety profile while the phase I and II clinical trials of another inhibitor AT-7519 have been undertaken or are undergoing. To enhance the effectiveness and target diversity and reduce potential drug-resistance, the future of CDK9 inhibition would likely involve combining CDK9 inhibitors with inhibitors like those against BRD4, SEC, MYC, MCL-1 and HSP90.

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 ]. 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.…”

“…CDKs 1–6 and 14–18 control cell cycle, whereas CDKs 7–13 regulate transcription [ 11 ]. Recent studies have shown a potential clinical benefit of targeting certain proteins from the CDK family in multiple neoplasms [ 12 ]. (Fig.…”

“…Whereas Cyclin K was shown to be upregulated through p53 activation suggesting its role in DNA repair due to stress [ 20 ]. The role of the CDK9 in cancer pathogenesis is not fully established yet, but several studies proved it to be a poor prognostic factor in various cancers [ 12 ]. CDK9 was shown to take part in c-MYC oncogene activation and Mcl-1 and Bcl-2 protein overexpression.…”

Management of Acute Myeloid Leukemia: Current Treatment Options and Future Perspectives

“…Cyclin dependent kinase 9 (CDK9) has emerged as a potential target in cancer [120]. Bogenberger and colleagues could demonstrate in vivo and in vitro significant synergistical effects between the CDK9 inhibitor alvocidib and venetoclax through affecting the balance of intrinsic apoptosis effectors, such as downregulation of MCl-1 and upregulation of BIM or NOXA [121].…”

Efficacy of CDK9 inhibition in therapy of post-myeloproliferative neoplasm (MPN) secondary (s) AML cells

“…CDK9 also phosphorylates and inactivates the negative transcription regulators NELF (negative elongation factor) and DSIF (DRB sensitivity-inducing factor), thereby further promoting RNAP2-mediated transcription [ 5 , 6 ]. CDK9 activity is required to maintain constant production of mRNAs of short-lived proteins, e.g., MCL1 and c-Myc, promoting growth and survival of AML cells [ 6 , 7 ]. Dysregulated c-Myc in AML cells, either due to amplification or protein stabilization, interacts with and recruits pTEFb to its own enhancers and promoter and those of its target genes to mediate RNAP2 pause-release [ 6 , 7 ].…”