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.