Identification of a Novel Selective CDK9 Inhibitor for the Treatment of CRC: Design, Synthesis, and Biological Activity Evaluation
Ye Zhong, Jing Xu, Ruochen Zhou, Li Tang, Shuo Ding, Zhaohui Ren, Ning Song, Baichun Hu, Huali Yang, Yili Sun, Maosheng Cheng, Jia Li, Yang Liu
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 (IC 50 = 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.