JAK1/JAK2 degraders based on PROTAC for topical treatment of atopic dermatitis.

ABSTRACT

Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disease. The Janus kinase (JAK) has been identified as a target in AD, as it regulates specific inflammatory genes and adaptive immune responses. However, the efficacy of topically applied JAK inhibitors in AD is limited due to the unique structure of skin. We synthesized JAK1/JAK2 degraders (JAPT) based on protein degradation targeting chimeras (PROTACs) and prepared them into topical preparations. JAPT exploited the E3 ligase to mediate ubiquitination and degradation of JAK1/JAK2, offering a promising AD therapeutic approach with low frequency and dosage. In vitro investigations demonstrated that JAPT effectively inhibited the release of pro-inflammatory cytokines and reduced inflammation by promoting the degradation of JAK. In vivo studies further confirmed the efficacy of JAPT in degrading JAK1/JAK2, leading to a significant suppression of type I, II, and III adaptive immunity. Additionally, JAPT demonstrated a remarkable reduction in AD severity, as evidenced by improved skin lesion clearance and AD severity scores (SCORAD). Our study revealed the therapeutic potential of JAPT, surpassing conventional JAK inhibitors in the treatment of AD, which suggested that JAPT could be a promising topically applied anti-AD drug targeting the JAK-STAT signaling pathway.