2. Academic Validation
  3. Rational Design of Dual Degraders by Incorporating Molecular Glue Structural Features into PROTAC Degraders

Rational Design of Dual Degraders by Incorporating Molecular Glue Structural Features into PROTAC Degraders

  • J Med Chem. 2025 May 22;68(10):10268-10298. doi: 10.1021/acs.jmedchem.5c00443.
Bowen Zhang 1,  Shan Gao 1,  Tingting Wu 1,  Yan Ma 1,  Senbiao Fang 2,  Mengyan Rong 1,  Wenrui Jia 1,  Sai Zhang 1 3,  Hui Hou 3,  Xiao Wang 1 3,  Siqi Zhang 3,  Chong Qin 1 3 4 2
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Educa-tion, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003, China.
  • 2 Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong 266071, China.
  • 3 Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong 266003, China.
  • 4 Laboratory for Marine Drugs and Bioproducts, Qingdao Ma-rine Science and Technology Center, Qingdao, Shandong 266137, China.
PMID: 40340418 DOI: 10.1021/acs.jmedchem.5c00443
Abstract

PROTAC and molecular glue present a novel therapeutic approach to tackle diseases propelled by the aberrant expression of disease-causing proteins. In this study, we identified a number of AR/AR-V7 and GSPT1 degraders that possess both PROTAC and molecular glue characteristics. The exploration of SAR led to the discovery of BWA-6047 as a potent degrader. BWA-6047 exhibited potent protein degradation in 22Rv1 cells (AR: DC50 = 3.7 nM, Dmax = 90%; AR-V7: DC50 = 3.0 nM, Dmax = 93%; GSPT1: DC50 = 1.2 nM, Dmax = 94%). Mechanism experiments indicate that BWA-6047 functions as both PROTAC and molecular glue to degrade target proteins. Oral administration of BWA-6047 at 20 mpk significantly inhibited LNCaP xenograft tumor growth in mice without obvious toxicity. Dual AR/AR-V7 and GSPT1 degraders represent a class of promising novel mechanism compounds for further extensive evaluations in prostate Cancer treatment.

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