<br>基于 PROTAC 的 JAK1/JAK2 降解剂用于局部治疗特应性皮炎,Biomedicine & Pharmacotherapy

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基于 PROTAC 的 JAK1/JAK2 降解剂用于局部治疗特应性皮炎
Biomedicine & Pharmacotherapy ( IF 6.9 ) Pub Date : 2024-01-22 , DOI: 10.1016/j.biopha.2024.116167
Junchao Wu ₁ , Lisha Li ₁ , Quangang Zhu ₁ , Tingrui Zhang ₂ , Fengze Miao ₂ , Zhen Cui ₂ , Guoqiang Dong ₃ , Zongguang Tai ₂ , Zhongjian Chen ₁

Affiliation

特应性皮炎（AD）是一种常见的慢性炎症性皮肤病。 Janus 激酶 (JAK) 已被确定为 AD 的靶标，因为它调节特定的炎症基因和适应性免疫反应。然而，由于皮肤的独特结构，局部应用 JAK 抑制剂治疗 AD 的疗效有限。我们基于蛋白质降解靶向嵌合体（PROTAC）合成了JAK1/JAK2降解剂（JAPT），并将其制备成外用制剂。 JAPT利用E3连接酶介导JAK1/JAK2的泛素化和降解，提供了一种有前途的低频率和剂量的AD治疗方法。体外研究表明，JAPT 可有效抑制促炎细胞因子的释放，通过促进 JAK 降解来减轻炎症。体内研究进一步证实了 JAPT 降解 JAK1/JAK2 的功效，从而显着抑制 I、II 和 III 型适应性免疫。此外，JAPT 证明 AD 严重程度显着降低，皮肤病变清除率和 AD 严重程度评分 (SCORAD) 的改善证明了这一点。我们的研究揭示了 JAPT 在治疗 AD 方面的治疗潜力，超越了传统的 JAK 抑制剂，这表明 JAPT 可能是一种有前途的局部应用的针对 JAK-STAT 信号通路的抗 AD 药物。

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

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.

更新日期：2024-01-22

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