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鉴定 1-吡唑并[3,4-b]吡啶衍生物为新型强效 TBK1 抑制剂：设计、合成、生物评价及分子对接研究。

Identification of 1-pyrazolo[3,4-b]pyridine derivatives as novel and potent TBK1 inhibitors: design, synthesis, biological evaluation, and molecular docking study.

机构信息

Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, P. R. China.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P. R. China.

出版信息

J Enzyme Inhib Med Chem. 2022 Dec;37(1):1411-1425. doi: 10.1080/14756366.2022.2076674.

DOI:10.1080/14756366.2022.2076674
PMID:35587686
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9132415/
Abstract

sABSTRACTTANK-binding kinase 1 (TBK1), a noncanonical member of the inhibitor-kappaB kinases (IKKs) family, plays a vital role in coordinating the signalling pathways of innate immunity, involving in the process of neuroinflammation, autophagy, and oncogenesis. In current study, based on rational drug design strategy, we discovered a series of 1-pyrazolo[3,4-b]pyridine derivatives as potent TBK1 inhibitors and dissected the structure-activity relationships (SARs). Through the several rounds of optimisation, compound stood out as a potent inhibitor on TBK1 with an IC value of 0.2 nM and also displayed good selectivity. The mRNA detection of TBK1 downstream genes showed that compound effectively inhibited TBK1 downstream IFN signalling in stimulated THP-1 and RAW264.7 cells. Meanwhile, compound exhibited a micromolar antiproliferation effect on A172, U87MG, A375, A2058, and Panc0504 cell lines. Together, current results provided a promising TBK1 inhibitor as lead compound for immune- and cancer-related drug discovery.

摘要

摘要 TANK 结合激酶 1（TBK1）作为 IKB 激酶（IKK）家族的非典型成员，在协调先天免疫信号通路方面发挥着重要作用，参与神经炎症、自噬和肿瘤发生过程。在本研究中，我们基于合理药物设计策略，发现了一系列 1-吡唑并[3,4-b]吡啶衍生物，它们是有效的 TBK1 抑制剂，并剖析了结构-活性关系（SAR）。通过几轮优化，化合物 脱颖而出，成为一种有效的 TBK1 抑制剂，IC 值为 0.2 nM，且具有良好的选择性。TBK1 下游基因的 mRNA 检测表明，化合物 在刺激的 THP-1 和 RAW264.7 细胞中能有效抑制 TBK1 下游 IFN 信号。同时，化合物 在 A172、U87MG、A375、A2058 和 Panc0504 细胞系中表现出微摩尔级的抗增殖作用。总之，本研究结果为免疫和癌症相关药物发现提供了一个有前景的 TBK1 抑制剂先导化合物 。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7965/9132415/99d64ccb510c/IENZ_A_2076674_F0009_C.jpg
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