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

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.