Identification of a Novel Selective CDK9 Inhibitor for the Treatment of CRC: Design, Synthesis, and Biological Activity Evaluation

  • J Med Chem. 2024 Mar 28;67(6):4739-4756. doi: 10.1021/acs.jmedchem.3c02329.
Ye Zhong  1 ,  Jing Xu  2  3 ,  Ruochen Zhou  4 ,  Li Tang  1 ,  Shaoyue Ding  1 ,  Zhaohui Ren  3 ,  Ning Song  3  5 ,  Baichun Hu  1 ,  Huali Yang  1 ,  Yili Sun  3  5 ,  Maosheng Cheng  1 ,  Jia Li  2  3  4  5 ,  Yang Liu  1
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2. Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • 3. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
  • 4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 5. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
PMID: 38488882 DOI: 10.1021/acs.jmedchem.3c02329
Abstract

Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily. In this work, we preliminarily demonstrated the feasibility of CDK9 as a potent target of treatment for Colorectal Cancer, and a series of novel CDK9 inhibitors were rationally designed and synthesized based on the structure of AZD5438 (a pan CDKs inhibitor reported by AstraZeneca). A novel selective CDK9 Inhibitor named CLZX-205, which possessed significant CDK9 inhibitory activity (IC50 = 2.9 nM) with acceptable pharmacokinetic properties and antitumor efficacy in vitro and in vivo, was developed. Research on the mechanism indicated that CLZX-205 could induce Apoptosis in the HCT116 cell line by inhibiting phosphorylation of RNA polymerase II at Ser2, which resulted in the inhibition of apoptosis-related genes and proteins expression, and these results were validated at the cellular and tumor tissue levels. Currently, CLZX-205 is undergoing further research as a promising candidate for CRC treatment.

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