鉴定靶向 TYK2 伪激酶结构域的小分子激活剂

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-08 DOI:10.1016/j.bmcl.2025.130233

Hirokazu Matsumoto , Tien-Cheng Wang , Haruka Taniguchi , Yu Nishioka , Mariko Hatakeyama , Takayoshi Kinoshita , Masaaki Sawa

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引用次数: 0

摘要

酪氨酸激酶2 （TYK2）在适应性和先天免疫反应中起着至关重要的作用。TYK2 JH1激酶结构域的催化活性受TYK2 JH2伪激酶结构域控制，并稳定维持其失活状态，直至上游受体激活。在这里，我们通过对已知的JH2结合剂进行结构修饰，发现了氨基吡啶类似物作为新型TYK2激活剂。化合物16b显示TYK2酶活性的剂量依赖性增加。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Identification of small molecule activators targeting TYK2 pseudokinase domain

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Identification of small molecule activators targeting TYK2 pseudokinase domain

Tyrosine kinase 2 (TYK2) plays a crucial role in both adaptive and innate immune responses. The catalytic activity of the TYK2 JH1 kinase domain is controlled by the TYK2 JH2 pseudokinase domain and stabilized to maintain its inactive state until the upstream receptor activations. Here, we report the discovery of aminopyridine analogs as novel TYK2 activators through structural modification of a known JH2 binder. Compound 16b demonstrated a dose-dependent increase in TYK2 enzymatic activity.

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.