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

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/cm2) for 1 min. Owing to the ERα degradation merit, MR3 displayed a 45-fold boosted anticancer activity (IC50 = 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.