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.