Discovery of ZJC-11 as a Novel Selective CDK7 Inhibitor for Treating Triple-Negative Breast Cancer by Inducing Cell Senescence
Bo Chen, Lihong Wu, Limei Zhang, Mingpu Liu, Jiecheng Zheng, Gang Wang, Yuanli Wu, Xiaojiao Chen, Manjialan Yin, Qinghua Hu, Guangxu Huang, Bowen Wang, Xinhong Tian, Zhengze Shen, Zongjie Gan, Weiying ZhouAbstract
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.