2. Academic Validation
  3. Discovery of a Novel Non-invasive AR PROTAC Degrader for the Topical Treatment of Androgenetic Alopecia

Discovery of a Novel Non-invasive AR PROTAC Degrader for the Topical Treatment of Androgenetic Alopecia

  • J Med Chem. 2024 Dec 26;67(24):22218-22244. doi: 10.1021/acs.jmedchem.4c02226.
Xinfei Mao 1,  Weitong Hu 2,  Mingfei Wu 1,  Yuyuan Jin 3,  Jingyi Zhao 1,  Yihua Xu 2,  Bizhi Li 1,  Wentao Wang 1,  Yiquan Wu 1,  Jingyu Zhang 1,  Ao Pang 1,  Yuheng Jin 1,  Tianyuan Zhang 2,  Wenhai Huang 3,  Jinxin Che 1 4,  Jianqing Gao 2 4 5,  Xiaowu Dong 1 4 5
Affiliations

Affiliations

  • 1 Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P.R. China.
  • 2 Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P.R. China.
  • 3 Center of Safety Evaluation and Research, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310059, P.R. China.
  • 4 State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310009, P.R. China.
  • 5 Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, P.R. China.
PMID: 39641607 DOI: 10.1021/acs.jmedchem.4c02226
Abstract

Elevated expression levels and enhanced activity of Androgen Receptor (AR) proteins are key factors in the development of androgenetic alopecia (AGA). AR proteolysis-targeting chimera (PROTAC) degraders have shown therapeutic potential, but their poor skin permeability requires invasive delivery methods. In this study, we conducted a structure feature analysis to investigate the effects of different linkers and E3 ligands of AR PROTACs on skin retention properties and degradation potency. Among these, compound C6 was discovered with excellent skin retention properties and nanomolar level AR degradation. By degrading AR, C6 regulated the expression levels of downstream paracrine factors associated with AGA. Additionally, after non-invasive topical application, C6 demonstrated excellent skin accumulation and achieved hair regeneration in an AGA mouse model. Overall, the development of non-invasive C6 offers a promising new strategy for AGA treatment and highlights the potential for using PROTACs in treating Other skin diseases.

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