Abstract
TRAF2- and NCK-interacting kinase (TNIK) represents one of the crucial targets for Wnt-activated colorectal cancer. In this study, we curated two datasets and conducted a comprehensive modeling study to explore novel TNIK inhibitors with desirable biopharmaceutical properties. With Dataset I, we derived Comparative Molecular Similarity Indices Analysis (CoMSIA) and variable-selection k-nearest neighbor models, from which 3D-molecular fields and 2D-descriptors critical for the TNIK inhibitor activity were revealed. Based on Dataset II, predictive CoMSIA-SIMCA (Soft Independent Modelling by Class Analogy) models were obtained and employed to screen 1,448 FDA-approved small molecule drugs. Upon experimental evaluations, we discovered that mebendazole, an approved anthelmintic drug, could selectively inhibit TNIK kinase activity with a dissociation constant Kd = ~1 μM. The subsequent CoMSIA and kNN analyses indicated that mebendazole bears the favorable molecular features that are needed to bind and inhibit TNIK.
Highlights
While numerous clinical-relevant kinase inhibitors have been approved[8,9], development of inhibitors targeting TRAF2- and NCK-interacting kinase (TNIK) is still in the very early stage
Experimental validation using the KINOMEscan platform[14] (Ambit Biosciences; http://www.kinomescan.com), we found that an anthelmintic drug, mebendazole, could selectively inhibited 91.8% of the TNIK signal at 10 μM, with a dissociation constant (Kd) of ~1 μM
As all compounds in Dataset I are thiazole-4-carboxamide derivatives (Fig. 1), it provides a reliable structural basis to perform ligand alignment for quantitative Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) studies
Summary
While numerous clinical-relevant kinase inhibitors have been approved[8,9], development of inhibitors targeting TNIK is still in the very early stage. Davis et al profiled the binding affinities of 72 known, chemically diverse kinase inhibitors against 442 kinases, and found a number of compounds exhibited significant binding to TNIK, with dissociation constant ranging from 4.7 nM to 8.5 μM (defined as Dataset II)[11]. We conducted 2D- and 3D-QSAR studies based on these two datasets and attempted to identify novel TNIK inhibitors with preferred biopharmaceutical properties. With Dataset I, we derived Comparative Molecular Field Analysis (CoMFA), Comparative Molecular Similarity Indices Analysis (CoMSIA), and variable-selection k-nearest neighbor (kNN) models, from which the 3D-molecular fields and 2D-descriptors critical for TNIK inhibitory activity were discovered. Experimental validation using the KINOMEscan platform[14] (Ambit Biosciences; http://www.kinomescan.com), we found that an anthelmintic drug, mebendazole, could selectively inhibited 91.8% of the TNIK signal at 10 μM, with a dissociation constant (Kd) of ~1 μM. This study represents a unique ligand-based framework for drug repurposing against a specific protein target critical for colorectal cancer treatment
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