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Issue 8, 2015
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Discovery of TRAF-2 and NCK-interacting kinase (TNIK) inhibitors by ligand-based virtual screening methods

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Abstract

TRAF-2 and NCK-interacting kinase (TNIK) is a serine–threonine kinase with a proposed role in Wnt/β-catenin and JNK pathways. Due to its implication in Wnt-mediated colorectal carcinogenesis, selective TNIK inhibition has emerged as an attractive anti-cancer therapeutic strategy. So far, only a few TNIK inhibitors have been described and none of them reached advanced preclinical development. In this study, a virtual screening approach was applied for the investigation of novel TNIK inhibitors. The best performing ShaEP methodology for similarity searching was applied for screening of a commercially available small-molecule database. Among several discovered TNIK kinase inhibitors, a compound containing the furan-2-carboxamide scaffold was found to be the most active, with IC50 = 0.85 μM. An advanced substructure search led to the discovery of a more potent and selective compound with IC50 = 258 nM. The most active compounds were tested in vitro for their effect on the Wnt/β-catenin pathway and proliferation of Wnt-active colorectal cancer cells. The compounds identified in this study represent attractive starting points for the development of more potent and selective small-molecule TNIK inhibitors for both therapeutic application and research into TNIK's biological role.

Graphical abstract: Discovery of TRAF-2 and NCK-interacting kinase (TNIK) inhibitors by ligand-based virtual screening methods

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Supplementary files

Article information


Submitted
03 Mar 2015
Accepted
24 Jun 2015
First published
24 Jun 2015

Med. Chem. Commun., 2015,6, 1564-1572
Article type
Concise Article
Author version available

Discovery of TRAF-2 and NCK-interacting kinase (TNIK) inhibitors by ligand-based virtual screening methods

A. Bujak, F. Stefaniak, D. Zdzalik, P. Grygielewicz, B. Dymek, M. Zagozda, P. Gunerka, M. Lamparska-Przybysz, K. Dubiel, M. Wieczorek and K. Dzwonek, Med. Chem. Commun., 2015, 6, 1564 DOI: 10.1039/C5MD00090D

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