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

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

  • J Med Chem. 2025 Apr 24;68(8):8861-8872. doi: 10.1021/acs.jmedchem.5c00490.
Yu Zhang 1 2,  Qiying Yu 3,  Ziwei Wang 2,  Luolong Qing 2,  Xiaoman Mo 2,  Bing Liu 2,  Yue'e Chai 4,  Bingqiong Yu 5,  Yongxi Dong 4,  Weidong Pan 1 2,  Silong Zhang 1 2,  Huan He 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), College of Life Sciences/Institute of Agro-bioengineering, Guizhou University, Guiyang 550025, Guizhou Province, China.
  • 2 Guizhou Engineering Laboratory for Synthetic Drugs, School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, P. R. China.
  • 3 Central Laboratory, Tumor Hospital Affiliated to Nantong University, Nantong 226361, Jiangsu, PR China.
  • 4 Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 561113, P. R. China.
  • 5 School of Pharmacy, Gannan Medical University, Ganzhou 341000, China.
PMID: 40213902 DOI: 10.1021/acs.jmedchem.5c00490
Abstract

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.

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