Discovery of an Androgen Receptor Degrader Featuring a Pyridazinyl Glutarimide CRBN-Binding Motif for Transdermal Treatment of Androgenetic Alopecia
Androgenetic alopecia (AGA) is primarily driven by overexpression of androgen receptor (AR) in hair follicles, leading to androgen hypersensitivity and progressive follicular miniaturization. Although PROTAC degraders offer the potential for sustained AR downregulation, their application in AGA has been limited by poor solubility and skin permeability. In this study, we incorporated pyridazinyl glutarimide (PDG) moiety as a novel CRBN ligand and developed dAR-6–1, a PROTAC with both potent AR degradation activity (DC50 = 0.90 nM, Dmax = 91% in LNCaP; DC50 = 0.23 nM, Dmax = 90% in hDPC) and exceptional aqueous solubility (S > 500 mg·mL–1). Both in vitro porcine skin permeation and in vivo mouse studies confirmed the favorable skin permeability of dAR-6–1. In the AGA mouse model, topical application of dAR-6–1 resulted in superior hair regeneration compared to minoxidil. These results establish dAR-6–1 as a promising candidate and provide a valuable design strategy for transdermal PROTACs.
Authors
- Chong Qin (ORCID: https://orcid.org/0000-0001-8108-1698)
- X Wang (ORCID: https://orcid.org/0009-0006-7225-4677)
- Tengjiang Zhong
- Zhuoyue Li (ORCID: https://orcid.org/0000-0002-2334-9059)
- Zhiyao Zhuang
- Yawei Yu
- Xi Zhang (ORCID: https://orcid.org/0000-0002-4638-3997)
- Xuan Chen (ORCID: https://orcid.org/0000-0001-5553-3638)
- Ling Ge
- Jianqing Gao (ORCID: https://orcid.org/0000-0003-1052-7060)
- Xiaolin Jiang
- Senbiao Fang
- W W Hu
- Tao Wang
- Huimin Chen
- Miaoyuan Yang
- Siqi Zhang (ORCID: https://orcid.org/0000-0001-8682-1683)
- Sai Zhang
Institutions
- Target (United States) (US)
- Qingdao National Laboratory for Marine Science and Technology (CN)
- Marine Biomedical Research Institute of Qingdao (CN)
- Ocean University of China (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-05-29
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c03843
- Primary Topic
- Hair Growth and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ocean University of China
- Natural Science Foundation of Shandong Province
- Polit National Laboratory for Marine Science and Technology
- Key Technology Research and Development Program of Shandong
- National Key Research and Development Program of China
- Key Research and Development Program of Zhejiang Province