Discovery of novel cycloalkyl-fused thiazole-based pyrimidine derivatives as highly potent CDK2 inhibitors with promising antitumor activity.

CDK2 has a pivotal role in the cell cycle process, and regulates a broad range of important biological processes, and recent investigations have revealed that inhibiting CDK2 can reverse cancer resistance to CDK4/6 inhibitors, indicating the therapeutic promise of CDK2 as an attractive therapeutic target in cancer treatment. Herein, we discovered a novel class of cycloalkyl-fused thiazole-substituted 2,4-diaminopyrimidine derivatives as potent CDK2 inhibitors. Especially, compound 12c significantly inhibited CDK2 (IC50 = 4.7 nM) which was 7-fold greater than positive control AZD5438, and exhibited remarkable antiproliferative efficacy toward HCT-116, A549, HeLa, and MCF-7 cells with the IC50s of 1.29-6.14 μM. Mechanism research revealed that 12c dose-dependently caused G2/M cell cycle arrest, and promoted apoptosis of HCT116. Overall, these findings present valuable leads and are of great importance to develop highly potent CDK2 inhibitors for cancer therapy.