4.7 Article

Combinatorial Virtual Screening Revealed a Novel Scaffold for TNKS Inhibition to Combat Colorectal Cancer

Journal

BIOMEDICINES
Volume 10, Issue 1, Pages -

Publisher

MDPI
DOI: 10.3390/biomedicines10010143

Keywords

TNKS inhibitor; virtual screening; pharmacophore; Wnt signaling pathway; docking; beta-catenin

Funding

  1. Tzu Chi Medical Mission Project [TCMMP 110-01]
  2. Buddhist Tzu Chi Medical Foundation
  3. Hualien Tzu Chi Hospital Research Project [TCRD110-30]

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This study focused on the abnormal Wnt signaling pathway and found that the inhibition of tankyrase (TNKS) activity can reduce cancer cell growth, invasion, and resistance to treatment. Through pharmacophore search and docking, potential TNKS inhibitors were identified and two of them were validated as promising inhibitors. Additionally, a cell-based assay revealed that one of the inhibitors is the most likely TNKS inhibitor and can effectively inhibit the growth of colorectal cancer cells.
The abnormal Wnt signaling pathway leads to a high expression of beta-catenin, which causes several types of cancer, particularly colorectal cancer (CRC). The inhibition of tankyrase (TNKS) activity can reduce cancer cell growth, invasion, and resistance to treatment by blocking the Wnt signaling pathway. A pharmacophore search and pharmacophore docking were performed to identify potential TNKS inhibitors in the training databases. The weighted MM/PBSA binding free energy of the docking model was calculated to rank the databases. The reranked results indicated that 26.98% of TNKS inhibitors that were present in the top 5% of compounds in the database and near an ideal value ranked 28.57%. The National Cancer Institute database was selected for formal virtual screening, and 11 potential TNKS inhibitors were identified. An enzyme-based experiment was performed to demonstrate that of the 11 potential TNKS inhibitors, NSC295092 and NSC319963 had the most potential. Finally, Wnt pathway analysis was performed through a cell-based assay, which indicated that NSC319963 is the most likely TNKS inhibitor (pIC(50) = 5.59). The antiproliferation assay demonstrated that NSC319963 can decrease colorectal cancer cell growth; therefore, the proposed method successfully identified a novel TNKS inhibitor that can alleviate CRC.

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