A Selective ERα Photodegrader for Precise and Efficient Breast Cancer Treatment

Abstract

Abstract 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.