A Selective ERα Photodegrader for Precise and Efficient Breast Cancer Treatment
Ziwei Wang, Xin Ding, Zhao Li, Yu Zhang, Qizhang Li, Kangkang Li, Jian Min, Juan Xu, Weidong Pan, Huan He, Chang Min, Silong ZhangAbstract
Breast cancer is the most prevalent malignancy in women, with over 70% of cases being estrogen receptor α (ERα)-positive. Photodynamic therapy (PDT) is spatially precise yet limited by tumor-selective photosensitizers. Herein, we report the first co-crystal structure of 2,2′-dihydroxytriphenylamine bound to ERα, which provided a structural blueprint for designing EP5, an innovative ERα-targeted photodegrader. EP5 exhibits high binding affinity toward ERα (KD = 56.7 nM), enabling its selective accumulation in ERα-positive breast cancer cells. Upon white-light irradiation, EP5 triggers selective ERα degradation without affecting ERβ. It potently suppresses ERα-positive cancer cell proliferation (IC50 = 0.54 μM, selectivity index >185). Systemic EP5 administration plus light achieves complete xenograft tumor regression (TGI = 105.3%) with no detectable systemic toxicity. EP5 is a promising candidate for precision breast cancer therapy. By simultaneously achieving tumor selectivity, therapeutic efficacy, and safety, EP5 represents a promising precision oncology platform for clinical translation.