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.
Sci Rep. 2016 Sep 21;6:33534. doi: 10.1038/srep33534.
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.
TRAF2 和 NCK 相互作用激酶（TNIK）是 Wnt 激活的结直肠癌的关键靶点之一。在这项研究中，我们整理了两个数据集，并进行了全面的建模研究，以探索具有理想的生物制药特性的新型 TNIK 抑制剂。使用数据集 I，我们得出了比较分子相似性指数分析（CoMSIA）和可变选择 k-最近邻模型，从中揭示了对 TNIK 抑制剂活性至关重要的 3D 分子场和 2D 描述符。基于数据集 II，获得了预测性 CoMSIA-SIMCA（类间软独立建模分析）模型，并将其用于筛选 1448 种已批准的 FDA 小分子药物。经过实验评估，我们发现苯并咪唑，一种已批准的驱虫药，能够以解离常数 Kd≈1μM 的方式选择性抑制 TNIK 激酶活性。随后的 CoMSIA 和 kNN 分析表明，苯并咪唑具有结合和抑制 TNIK 所需的有利分子特征。
