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

Lanshu Xiao; Yi Liu; Hui Chen; Lisong Shen

doi:10.1080/15384047.2023.2219470

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

Cancer Biol Ther. 2023 Dec 31;24(1):2219470. doi: 10.1080/15384047.2023.2219470.

Authors

Lanshu Xiao^{1

2}, Yi Liu¹, Hui Chen¹, Lisong Shen^{1

2

3}

Affiliations

¹ Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China.

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.

Keywords: CDK9; PROTAC degraders; development; small molecular inhibitors; targeted therapy; tumor.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Cyclin-Dependent Kinase 9* / chemistry
Cyclin-Dependent Kinase 9* / genetics
Humans
Neoplasms* / drug therapy
Positive Transcriptional Elongation Factor B

Substances

Cyclin-Dependent Kinase 9
Positive Transcriptional Elongation Factor B
CDK9 protein, human

Grants and funding

This project was supported by grants from the National Natural Science Foundation of China (grant numbers 81874152, 81903038, 81402332, 81372641, and 81672363) to Lisong Shen, Hui Chen, and Yi Liu, the Shanghai Key Clinical Specialty Construction Project (grant number shslczdzk03304) to Lisong Shen, and the Shanghai Sailing Program (grant number 19YF1432700) to Yi Liu.