Discovery of a\nNovel Non-invasive AR PROTAC Degrader\nfor the Topical Treatment of Androgenetic Alopecia

Elevated\nexpression levels and enhanced activity of androgen receptor\n(AR) proteins are key factors in the development of androgenetic alopecia\n(AGA). AR proteolysis-targeting chimera (PROTAC) degraders have shown\ntherapeutic potential, but their poor skin permeability requires invasive\ndelivery methods. In this study, we conducted a structure feature\nanalysis to investigate the effects of different linkers and E3 ligands\nof AR PROTACs on skin retention properties and degradation potency.\nAmong these, compound <b>C6</b> was discovered with excellent\nskin retention properties and nanomolar level AR degradation. By degrading\nAR, <b>C6</b> regulated the expression levels of downstream\nparacrine factors associated with AGA. Additionally, after non-invasive\ntopical application, <b>C6</b> demonstrated excellent skin accumulation\nand achieved hair regeneration in an AGA mouse model. Overall, the\ndevelopment of non-invasive <b>C6</b> offers a promising new\nstrategy for AGA treatment and highlights the potential for using\nPROTACs in treating other skin diseases.