Discovery of ZJC-11 as a Novel Selective CDK7 Inhibitor for Treating Triple-Negative Breast Cancer by Inducing Cell Senescence.

The development of cyclin-dependent kinase 7 (CDK7) inhibitors represents a promising therapeutic strategy for triple-negative breast cancer (TNBC). Herein, we designed and synthesized 21 novel CDK7-targeted small molecules and identified ZJC-11 as a potent lead candidate. ZJC-11 demonstrated significant antiproliferative activity against TNBC both in vitro and in vivo, with reduced toxicity compared to the reported CDK7 inhibitor THZ1. Molecular docking, Kinact/KI tests, kinase selectivity profiling, and pharmacokinetic studies confirmed that ZJC-11 selectively and covalently targets CDK7 with favorable pharmacokinetic properties. RNA sequencing and functional analyses revealed that ZJC-11 not only suppresses transcription and G2/M cell cycle checkpoint pathways but also induces DNA damage-driven cellular senescence, ultimately leading to TNBC cell death. Moreover, ZJC-11 not only exhibited a synergistic anti-TNBC effect when combined with doxorubicin but also alleviated doxorubicin-induced cardiotoxicity, a clinically significant adverse effect, highlighting its promise as a therapeutic candidate for TNBC treatment.