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.

雄激素受体（androgen receptor, AR）蛋白的表达上调与活性增强，是雄激素性脱发（androgenetic alopecia, AGA）发生发展的关键驱动因素。蛋白水解靶向嵌合体（proteolysis-targeting chimera, PROTAC）类AR降解剂已展现出治疗潜力，但其皮肤渗透性不佳，需依赖侵入式递送手段。本研究通过结构特征分析，探究了AR PROTAC的不同连接子与E3配体对其皮肤滞留特性及降解效力的影响。其中，化合物C6被证实具备优异的皮肤滞留性能与纳摩尔级的AR降解活性。通过降解AR，C6可调控与AGA相关的下游旁分泌因子的表达水平。此外，经非侵入性局部外用给药后，C6展现出出色的皮肤蓄积能力，并在AGA小鼠模型中实现了毛发再生。总体而言，非侵入性递送的C6为AGA治疗提供了极具前景的全新策略，同时也凸显了PROTAC类降解剂在治疗其他皮肤疾病方面的应用潜力。