Design, synthesis and biological assessment of novel CDK4 inhibitor with potent anticancer activity.

Efforts toward finding potent CDK4 inhibitor for cancer therapy, a series of fluorine substituted pyrrolo[2,3-d]pyrimidine derivatives were designed, synthesized, and evaluated. Among them, the optimal lead compound 18i was discovered with potent activity against CDK4 at the nanomolar level (IC50 = 2.5 nM) and exquisite selectivity which demonstrated only modest activity against 3 out of the 394 protein kinases. 18i exhibited a much greater in vitro antiproliferative activity against several human cancer cell lines than that of the approved drug ribociclib. Further mechanism studies revealed that 18i effectively stimulated cancer cell cycle arrest in G1 phase and induced tumor cell apoptosis. In the comparison of in vivo therapeutic effects in xenograft mouse models of breast cancer, oral administration of 18i showed a significantly better degree of inhibitory effect to ribociclib without obvious toxicity. All of the results indicated that 18i could be a promising CDK4 inhibitor for treating malignancies.