Discovery of new imidazole[1,2-a] pyridine derivatives as CDK9 inhibitors: design, synthesis and biological evaluation

Colorectal cancer (CRC) is a highly aggressive and extensive malignancy. Presently, targeting the transcriptional regulation of cyclin-dependent kinase 9 (CDK9) is a promising therapeutic approach. Herein, twenty-five compounds (LA-1-LA-13 and LB-1-LB-12) were designed and synthesized with AZD5438 as the lead compound using an imidazole[1,2-a] pyridine skeleton. Compound LB-1 exhibited potent CDK9 inhibition and induced apoptosis in the HCT116 cell line. Moreover, compared with AZD5438, LB-1 demonstrated highly selective CDK9 inhibitory activity, with an IC₅₀ value of 9.22 nM. Accordingly, compound LB-1 could be further developed as a selective, target-oriented CDK9 inhibitor for colorectal cancer.