Discovery of a series of 1H-pyrrolo[2,3-b]pyridine compounds as potent TNIK inhibitors

Bowen Yang; Qian Wu; Xiajuan Huan; Yingqing Wang; Yin Sun; Yueyue Yang; Tongchao Liu; Xin Wang; Lin Chen; Bing Xiong; Dongmei Zhao; Zehong Miao; Danqi Chen

doi:10.1016/j.bmcl.2020.127749

Discovery of a series of 1H-pyrrolo[2,3-b]pyridine compounds as potent TNIK inhibitors

Bioorg Med Chem Lett. 2021 Feb 1:33:127749. doi: 10.1016/j.bmcl.2020.127749. Epub 2020 Dec 24.

Authors

Bowen Yang¹, Qian Wu², Xiajuan Huan², Yingqing Wang², Yin Sun³, Yueyue Yang⁴, Tongchao Liu⁴, Xin Wang⁴, Lin Chen⁴, Bing Xiong⁴, Dongmei Zhao⁵, Zehong Miao⁶, Danqi Chen⁷

Affiliations

¹ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
² Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
³ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
⁴ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
⁵ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: medchemzhao@163.com.
⁶ Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China. Electronic address: zhmiao@simm.ac.cn.
⁷ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: dqchen@simm.ac.cn.

PMID: 33340663
DOI: 10.1016/j.bmcl.2020.127749

Abstract

In an in-house screening, 1H-pyrrolo[2,3-b]pyridine scaffold was found to have high inhibition on TNIK. Several series of compounds were designed and synthesized, among which some compounds had potent TNIK inhibition with IC₅₀ values lower than 1 nM. Some compounds showed concentration-dependent characteristics of IL-2 inhibition. These results provided new applications of TNIK inhibitors and new prospects of TNIK as a drug target.

Keywords: 1H-pyrrolo[2,3-b]pyridine; IL-2 secretion inhibitory; TNIK inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyridines
Pyrroles
Protein Serine-Threonine Kinases
TNIK protein, human
pyrrolo(2, 3-b)pyridine