2. Academic Validation
  3. Discovery of an Androgen Receptor Degrader Featuring a Pyridazinyl Glutarimide CRBN-Binding Motif for Transdermal Treatment of Androgenetic Alopecia

Discovery of an Androgen Receptor Degrader Featuring a Pyridazinyl Glutarimide CRBN-Binding Motif for Transdermal Treatment of Androgenetic Alopecia

  • J Med Chem. 2026 Jun 11;69(11):13028-13054. doi: 10.1021/acs.jmedchem.5c03843.
Xiao Wang 1 2,  Ling Ge 1,  Yawei Yu 3,  Tengjiang Zhong 4,  Weitong Hu 3,  Sai Zhang 1 2 4,  Xuan Chen 1,  Miaoyuan Yang 1,  Xinxin Zhang 1,  Zhuoyue Li 1 2 4,  Zhiyao Zhuang 1,  Siqi Zhang 2,  Xiaolin Jiang 1,  Tao Wang 2,  Huimin Chen 2,  Senbiao Fang 4,  Jianqing Gao 3,  Chong Qin 1 2 4 5
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003, China.
  • 2 Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong 266003, China.
  • 3 Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 4 Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong 266071, China.
  • 5 Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, Shandong 266137, China.
PMID: 42213035 DOI: 10.1021/acs.jmedchem.5c03843
Abstract

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.

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