Rational Design of Dual Degraders by Incorporating Molecular Glue Structural Features into PROTAC Degraders
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 <b>BWA-6047</b> as a potent degrader. <b>BWA-6047</b> exhibited potent protein degradation in 22Rv1 cells (AR: DC<sub>50</sub> = 3.7 nM, <i>D</i><sub>max</sub> = 90%; AR-V7: DC<sub>50</sub> = 3.0 nM, <i>D</i><sub>max</sub> = 93%; GSPT1: DC<sub>50</sub> = 1.2 nM, <i>D</i><sub>max</sub> = 94%). Mechanism experiments indicate that <b>BWA-6047</b> functions as both PROTAC and molecular glue to degrade target proteins. Oral administration of <b>BWA-6047</b> 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.
Authors
- Chong Qin (ORCID: https://orcid.org/0000-0001-8108-1698)
- Yan Ma (ORCID: https://orcid.org/0000-0002-5924-1293)
- Wenrui Jia (ORCID: https://orcid.org/0000-0003-0928-0005)
- Hui Hou (ORCID: https://orcid.org/0009-0006-3484-7279)
- Xiao Wang (ORCID: https://orcid.org/0000-0001-7364-2459)
- Shan Gao (ORCID: https://orcid.org/0000-0003-1066-0531)
- Sai Zhang (ORCID: https://orcid.org/0000-0002-8028-4183)
- Bowen Zhang (ORCID: https://orcid.org/0000-0003-0432-745X)
- Siqi Zhang (ORCID: https://orcid.org/0000-0001-8682-1683)
- Ting-Ting Wu
- Senbiao Fang
- Mengyan Rong
Institutions
- Target (United States) (US)
- Marine Biomedical Research Institute of Qingdao (CN)
- Ocean University of China (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-05-09
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00443
- Citations
- 9
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 7.25
Funders
- Ocean University of China
- Qingdao National Laboratory for Marine Science and Technology
- Key Technology Research and Development Program of Shandong
- National Outstanding Youth Science Fund Project of National Natural Science Foundation of China
- Natural Science Fund for Distinguished Young Scholars of Shandong Province
- National Key Research and Development Program of China