Combinatorial Virtual Screening Revealed a Novel Scaffold for TNKS Inhibition to Combat Colorectal Cancer
Chun-Chun Chang1,2, Sheng-Feng Pan3, Min-Huang Wu2
1Department of Laboratory Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97004, Taiwan.
Abstract:
The abnormal Wnt signaling pathway leads to a high expression of β-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 (pIC50 = 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.
Insights
Researchers identified a novel tankyrase (TNKS) inhibitor, NSC319963, to combat colorectal cancer (CRC). This compound effectively reduces CRC cell growth by blocking the Wnt signaling pathway, offering a new therapeutic avenue.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Aberrant Wnt signaling pathway activity, marked by elevated β-catenin, drives various cancers, notably colorectal cancer (CRC).
- Tankyrase (TNKS) inhibition presents a therapeutic strategy to impede Wnt signaling, thereby reducing cancer progression and treatment resistance.
Purpose of the Study:
- To identify novel tankyrase (TNKS) inhibitors for potential colorectal cancer (CRC) therapy.
- To validate the efficacy of identified inhibitors through experimental assays.
Main Methods:
- Utilized pharmacophore searching and docking to screen compound databases for potential TNKS inhibitors.
- Employed weighted MM/PBSA binding free energy calculations for ranking potential inhibitors.
- Conducted enzyme-based and cell-based assays to validate TNKS inhibition and antiproliferative effects.
Main Results:
- Virtual screening identified 11 potential TNKS inhibitors from the National Cancer Institute database.
- Enzyme assays highlighted NSC295092 and NSC319963 as promising candidates.
- Cell-based assays confirmed NSC319963 as a potent TNKS inhibitor (pIC50 = 5.59) with significant antiproliferative activity against CRC cells.
Conclusions:
- The study successfully identified NSC319963 as a novel TNKS inhibitor with potential for colorectal cancer (CRC) treatment.
- NSC319963 demonstrates efficacy in reducing CRC cell proliferation by modulating the Wnt pathway.
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