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Targeting CDK9 with selective inhibitors or degraders in tumor therapy: an overview of recent developments.

ABSTRACT: As a catalytic subunit of the positive transcription elongation factor b (P-TEFb), cyclin-dependent kinase 9 (CDK9) has been demonstrated to contribute to carcinogenesis. This review focuses on the development of selective CDK9 inhibitors and proteolysis-targeting chimera (PROTAC) degraders. Twenty selective CDK9 inhibitors and degraders are introduced along with their structures, IC50 values, in vitro and in vivo experiments, mechanisms underlying their inhibitory effects, and combination regimens. NVP-2, MC180295, fadraciclib, KB-0742, LZT-106, and 21e have been developed mainly for treating solid tumors, and most of them work only on certain genotypes of solid tumors. Only VIP152 has been proven to benefit the patients with advanced high-grade lymphoma (HGL) and solid tumors in clinical trials. Continued efforts to explore the molecular mechanisms underlying the inhibitory effects, and to identify suitable tumor genotypes and combination treatment strategies, are crucial to demonstrate the efficacy of selective CDK9 inhibitors and degraders in tumor therapy.

SUBMITTER: Xiao L

PROVIDER: S-EPMC10243401 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Targeting CDK9 with selective inhibitors or degraders in tumor therapy: an overview of recent developments.

Xiao Lanshu L Liu Yi Y Chen Hui H Shen Lisong L

Cancer biology & therapy 20231201 1

As a catalytic subunit of the positive transcription elongation factor b (P-TEFb), cyclin-dependent kinase 9 (CDK9) has been demonstrated to contribute to carcinogenesis. This review focuses on the development of selective CDK9 inhibitors and proteolysis-targeting chimera (PROTAC) degraders. Twenty selective CDK9 inhibitors and degraders are introduced along with their structures, IC50 values, in vitro and in vivo experiments, mechanisms underlying their inhibitory effects, and combination regim ...[more]

PMID: 37272701

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Project description:Dysregulated cell division, which leads to aberrant cell proliferation, is one of the key hallmarks of cancer. Therefore, therapeutic targets that block cell division would be effective for cancer treatment. Cell division is mainly controlled by a complex composed of cyclin and cyclin dependent kinases (CDKs). To date, the CDK inhibitors (CDKIs), specifically the ones that block the enzyme activity of CDK4 and CDK6 (CDK4/6), have been approved by FDA for the treatment of metastatic hormone receptor positive breast cancer. However, due to the non-selectivity and significant toxicity, most of the first generation CDK inhibitors (so called pan-CDK inhibitors that target several CDKs), have not been approved for clinical application. Despite this, great efforts and progress have been made to enable pan-CDK inhibitors application in the clinical setting. Notably, the development of combination therapy strategies in recent years has made it possible to reduce the toxicity and side effects of pan-CDK inhibitors. Thus, as a combination therapy approach, pan-CDK inhibitors regain great potential in clinical application. In this review, we introduced the CDK family members and discussed their major functions in cell cycle controlling. Then, we summarized the research progress regarding CDK inhibitors, especially those other than CDK4/6 inhibitors. We reviewed first-generation pan-CDKIs Flavopiridol and Roscovitine, and second-generation CDKIs Dinaciclib, P276-00, AT7519, TG02, Roniciclib, RGB-286638 by focusing on their developing stages, clinical trials and targeting cancers. The specific CDKIs, which targets to increase specificity and decrease the side effects, were also discussed. These CDKIs include CDK4/6, CDK7, CDK9, and CDK12/13 inhibitors. Finally, the efficacy and discrepancy of combination therapy with CDK inhibitors and PD1/PDL1 antibodies were analyzed, which might give insights into the development of promising strategy for cancer treatment.

Dataset Information

Targeting CDK9 with selective inhibitors or degraders in tumor therapy: an overview of recent developments.

Publications

Targeting CDK9 with selective inhibitors or degraders in tumor therapy: an overview of recent developments.

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