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

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.