Abstract

sABSTRACT

TANK-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 1H-pyrazolo[3,4-b]pyridine derivatives as potent TBK1 inhibitors and dissected the structure–activity relationships (SARs). Through the several rounds of optimisation, compound 15y stood out as a potent inhibitor on TBK1 with an IC50 value of 0.2 nM and also displayed good selectivity. The mRNA detection of TBK1 downstream genes showed that compound 15y effectively inhibited TBK1 downstream IFN signalling in stimulated THP-1 and RAW264.7 cells. Meanwhile, compound 15y exhibited a micromolar antiproliferation effect on A172, U87MG, A375, A2058, and Panc0504 cell lines. Together, current results provided a promising TBK1 inhibitor 15y as lead compound for immune- and cancer-related drug discovery.

Details

Title
Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as novel and potent TBK1 inhibitors: design, synthesis, biological evaluation, and molecular docking study
Author
Sun, Yin 1 ; Tang, Haotian 2 ; Wang, Xiaoyan 1 ; Fang, Feng 3 ; Fan, Tiantian 2 ; Zhao, Dongmei 4 ; Xiong, Bing 2 ; Xie, Hua 5 ; Liu, Tongchao 3 

1  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 
2  Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , P. R. China, University of Chinese Academy of Sciences , Beijing , P. R. China 
3  Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , P. R. China 
4  Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University , Shenyang , P. R. China 
5  Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , P. R. China, University of Chinese Academy of Sciences , Beijing , P. R. China, Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , P. R. China 
Pages
1411-1425
Publication year
2022
Publication date
Dec 2022
Publisher
Taylor & Francis Ltd.
ISSN
14756366
e-ISSN
14756374
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1080/14756366.2022.2076674
ProQuest document ID
2727916006
Copyright
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.. This work is licensed under the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.