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 (<b>MR1</b>-<b>MR3</b>) by conjugating methylene blue, a bifunctional photosensitizer, with the raloxifene pharmacophore. The lead compound <b>MR3</b> 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, <b>MR3</b> displayed a 45-fold boosted anticancer activity (IC₅₀ = 0.55 μM) after irradiation. In the breast cancer xenograft mouse model, <b>MR3</b> induced an obvious tumor regression (tumor growth inhibition = 118%), which was superior to that of the FDA-approved ERα degrader <b>Faslodex</b>. These important features make <b>MR3</b> extremely intriguing for breast cancer treatment.