设计一种强效和选择性双重 JAK1/TYK2 抑制剂。

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2024-09-30 DOI:10.1016/j.bmc.2024.117932

Oscar Mammoliti , Christel Menet , Céline Cottereaux , Javier Blanc , Ann De Blieck , Ghjuvanni Coti , Raphaël Geney , Line Oste , Koen Ostyn , Adeline Palisse , Evelyne Quinton , Benoit Schmitt , Monica Borgonovi , Isabelle Parent , Catherine Jagerschmidt , Steve De Vos , Béatrice Vayssiere , Miriam López-Ramos , Kenji Shoji , Reginald Brys , Caroline Joannesse

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引用次数: 0

摘要

Janus 激酶（JAK）抑制剂作为几种炎症和自身免疫性疾病的治疗方法已引起人们的兴趣。首批上市的四种抑制剂以 JAK1 为靶点，对其他 JAK 家族成员有不同的选择性，但没有一种抑制剂能以临床相关剂量抑制酪氨酸激酶-2 (TYK2)。TYK2是白细胞介素（IL）-12和IL-23细胞因子信号转导所必需的，这两种细胞因子分别是TH1和TH17细胞极化的关键；这两种细胞亚型在炎症性疾病中发挥着重要作用。在此，我们报告了从 HTS 发现的新药开始，我们为优化强效和选择性双重 JAK1/TYK2 抑制剂系列所做的努力。结构信息揭示了提高 JAK1 和 TYK2 效力以及对 JAK2 选择性所需的载体。我们优化的先导化合物在生化试验中对 JAK1（3.5 nM）和 TYK2（5.7 nM）都有强效抑制作用，而且对 JAK2 有显著的选择性，这在细胞和全血试验中得到了证实。在 IL-23 诱导的银屑病样炎症小鼠模型中，先导化合物对 TYK2 的抑制作用表现为剂量依赖性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Design of a potent and selective dual JAK1/TYK2 inhibitor

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Design of a potent and selective dual JAK1/TYK2 inhibitor

Janus kinase (JAK) inhibitors have gathered interest as treatments for several inflammatory and autoimmune diseases. The four first marketed inhibitors target JAK1, with varying selectivity towards other JAK family members, but none inhibit tyrosine kinase-2 (TYK2) at clinically relevant doses. TYK2 is required for the signaling of the interleukin (IL)-12 and IL-23 cytokines, which are key to the polarization of T_H1 and T_H17 cells, respectively; two cell subtypes that play major roles in inflammatory diseases. Herein, we report our effort towards the optimization of a potent and selective dual JAK1/TYK2 inhibitor series starting from a HTS hit. Structural information revealed vectors required to improve both JAK1 and TYK2 potency as well as selectivity towards JAK2. The potent inhibition of both JAK1 (3.5 nM) and TYK2 (5.7 nM) in biochemical assays by our optimized lead compound, as well as its notable selectivity against JAK2, were confirmed in cellular and whole blood assays. Inhibition of TYK2 by the lead compound was demonstrated by dose-dependent efficacy in an IL-23-induced psoriasis-like inflammation mouse model.

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.