title: Comprehensive Modeling and Discovery of Mebendazole as a Novel TRAF2- and NCK-interacting Kinase Inhibitor.
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.
authors.affiliation: Integrated Molecular Discovery Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Integrated Molecular Discovery Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Integrated Molecular Discovery Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Shuxing
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000069439:Dasatinib / Q000494:pharmacology; D055808:Drug Discovery; D000081410:Germinal Center Kinases; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008463:Mebendazole / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*
chemical_list: D000081410:Germinal Center Kinases; D008024:Ligands; D047428:Protein Kinase Inhibitors; D047992:TNF Receptor-Associated Factor 2; D008463:Mebendazole; D017346:Protein Serine-Threonine Kinases; C000631454:TNIK protein, human; D000069439:Dasatinib