Discovery of novel CDK9 inhibitor with tridentate ligand: Design, synthesis and biological evaluation

[Display omitted] •A series of novel CDK9 inhibitor with tridentate ligand were designed and synthesized.•The unique tridentate ligand structure endows better CDK9 inhibition selectivity compared to other CDK subtypes.•Lead candidate Z4-7a showed effective proliferation inhibition in HCT116 cells with acceptable PK properties.•Z4-7a induced apoptosis effects on HCT116 cells. Cyclin-dependent kinase 9 (CDK9) plays a role in transcriptional regulation, which had become an attractive target for discovery of antitumor agent. In this work, beyond traditional CDK9 inhibitor with bidentate ligands in ATP binding domain, a series of novel CDK9 inhibitor with tridentate ligand were designed and synthesized. Surprisingly, this unique tridentate ligand structure endows better CDK9 inhibition selectivity compared to other CDK subtypes, and the lead candidate compound Z4-7a showed effective proliferation inhibition in HCT116 cells with acceptable pharmacokinetic properties. Research on the mechanism indicated that Z4-7a 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. In brief, introduction of tridentate ligand might work as a promising strategy for the development of novel selective CDK9 inhibitor.