NCP07: A potent ERα CBS-targeted degrader with dual-action against ESR1 mutations in breast cancer.

ESR1 mutation-driven endocrine therapy (ET) resistance remains a major challenge in breast cancer therapy. Herein, by integrating the advantages of PROTAC technology and coactivator-binding site (CBS) targeting strategy in overcoming drug resistance, we developed a class of novel and potent ERα PROTAC degraders against ET-resistant breast cancer. Among them, compound NCP07 could potently degrade ERα and inhibited proliferation (IC50 = 0.13-1.22 μM) in both wild-type and ESR1-mutated cell lines. Mechanistic studies confirmed that compound NCP07 could not only specifically bind to CBS followed by inducing the formation of ERα-NCP07-VHL ternary complex, but also induce apoptosis and cell cycle arrest in drug-resistant cells. Besides, compound NCP07 also exhibited favorable metabolic stability and high safety properties. Totally, the potent anti-breast cancer activity and favorable metabolic stability of compound NCP07 not only indicated that PROTAC degrader targeting ERα CBS was an effective dual-action strategy for overcoming ESR1 mutation, but also was a promising candidate for further developing potent drugs against ET-resistant breast cancer.