Development of a TBK1 and ALK dual inhibitor for alleviating depressive behavior via anti-inflammatory effects

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy Pub Date : 2025-03-20 DOI:10.1016/j.biopha.2025.117991

Ji Hun Wi , Hyelim Lee , Ji Min Park , Yeonju Heo , Seongman Jo , Jeehee Lee , Yeseul Kim , Cheulhee Jung , Nam-Jung Kim , Gyu Yong Song , Pilho Kim , Hyejin Kim , Sanghee Lee

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Abstract

Polypharmacology offers innovative strategies for treating immune and inflammatory dysregulation in complex diseases. Here, we identified ALS-04, a dual inhibitor of TANK-binding kinase 1 (TBK1) and anaplastic lymphoma kinase (ALK), which are closely linked to stimulator of interferon genes (STING)-mediated immune responses. ALS-04 effectively suppressed 2’3’-cyclic GMP-AMP (cGAMP)- and lipopolysaccharide (LPS)-induced type I interferon and pro-inflammatory responses by targeting the STING-TBK1 and STING-ALK pathways. Furthermore, ALS-04 significantly alleviated depressive symptoms, including anhedonia and behavioral despair, in an LPS-induced mouse model of depression. These findings highlight the therapeutic potential of dual TBK1 and ALK inhibition in depression by modulating immune and inflammatory pathways.

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TBK1和ALK双抑制剂通过抗炎作用减轻抑郁行为的发展。

多种药理学为治疗复杂疾病中的免疫和炎症失调提供了创新的策略。在这里，我们发现了ALS-04，一种坦克结合激酶1 （TBK1）和间变性淋巴瘤激酶（ALK）的双重抑制剂，它们与干扰素基因刺激因子（STING）介导的免疫反应密切相关。ALS-04通过靶向STING-TBK1和STING-ALK通路，有效抑制2'3'-环GMP-AMP (cGAMP)-和脂多糖（LPS）诱导的I型干扰素和促炎反应。此外，在lps诱导的抑郁小鼠模型中，ALS-04显著缓解抑郁症状，包括快感缺乏和行为绝望。这些发现强调了TBK1和ALK双重抑制通过调节免疫和炎症途径治疗抑郁症的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biomedicine & Pharmacotherapy 医学-药学

CiteScore

11.90

自引率

2.70%

发文量

1621

审稿时长

48 days

期刊介绍： Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.