Rational Design of Methylene Blue–Raloxifene Conjugates for Efficient Breast Tumor Elimination Triggered by ERα Degradation

作者：Yu Zhang, Qiying Yu, Ziwei Wang, Luolong Qing, Xiaokui Mo, Bing Liu, Yoke Chin Chai, Bingqiong Yu, Yongxi Dong, Weidong Pan, Silong Zhang, Huan He · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00490 · 被引用次数：9 · 研究领域：Click Chemistry and Applications、Protein Degradation and Inhibitors、Advanced biosensing and bioanalysis techniques

Small molecules capable of degrading estrogen receptor α (ERα) are of significant interest in breast cancer treatment. Herein, we rationally designed a series of ERα degraders ( MR1 – MR3 ) by conjugating methylene blue, a bifunctional photosensitizer, with the raloxifene pharmacophore. The lead compound MR3 exhibited high affinity to ERα, and it can induce a complete depletion of ERα in MCF7 breast cancer cells after 660 nm irradiation (0.4 W/cm 2 ) for 1 min. Owing to the ERα degradation merit, MR3 displayed a 45-fold boosted anticancer activity (IC 50 = 0.55 μM) after irradiation. In the breast cancer xenograft mouse model, MR3 induced an obvious tumor regression (tumor growth inhibition = 118%), which was superior to that of the FDA-approved ERα degrader Faslodex . These important features make MR3 extremely intriguing for breast cancer treatment.