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
  • 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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