Discovery of azaindole/indole-fused pyrimidine tetracyclic scaffolds as novel potent CDK7 inhibitors.

CDK7 has emerged as a highly promising anticancer target, as its dual indispensable roles in cell cycle progression and transcriptional regulation for cancer cell proliferation and survival. Herein, we describe the rational design and identification of novel tetracyclic CDK7 inhibitors with an azaindole/indole-fused pyrimidine scaffold, achieved via a cyclisation-based conformational restriction strategy. Compound 7a emerged as a potent, highly selective CDK7 inhibitor (IC50 = 1.9 nM), outperforming clinical candidate SY-5609 (IC50 = 2.5 nM). It exhibited prominent antiproliferative activity against HCT116 colorectal cancer cells (IC50 = 1.7 nM) and excellent selectivity over other CDK isoforms.

In vivo, 7a exerted robust dose-dependent antitumor efficacy in HCT116 xenograft model without obvious toxicity. Collectively, its superior in vitro potency, high CDK7 selectivity, and significant in vivo antitumor activity highlight the potential of 7a as a chemical tool for investigating CDK7 biology and as a lead compound for further pharmacokinetic optimisation.