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Updated: May 5, 2026
A Fluorescence-based Lymphocyte Assay Suitable for High-throughput Screening of Small Molecules
Published on: March 10, 2017
High-Throughput Screening Tool to Identify Small Molecule Inhibitors of Telomerase
Elisa Aquilanti1,2, Sulyman Barkho3, Vincent Bozinov2
1Division of Neuro Oncology, Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, United States.
Abstract:
Telomerase reverse transcriptase is a ribonucleoprotein complex that maintains telomere length in rapidly dividing cells, thus enabling cellular immortality. Despite being recognized as an important cancer target for decades, no small molecule telomerase inhibitors have been approved as anticancer therapeutics to date. Several limitations, including the absence of high-throughput screening tools, have posed challenges to the telomerase drug discovery field. Here, we describe a high-throughput, fluorescently coupled screening method employing a chemically modified reporter nucleotide. We utilize the Tribolium castaneum telomerase as a surrogate model as it shares a high degree of active site homology with the human enzyme. We piloted this tool by screening a chemical library of ∼3600 nucleoside mimetics to demonstrate excellent assay quality, and identified 2 compounds with inhibitory activity that were further validated in a direct enzymatic assay. Our work introduces a method that has the potential to uncover novel telomerase inhibitors for further drug discovery efforts.
Insights
Researchers developed a new high-throughput screening method to find telomerase inhibitors. This assay, using a modified nucleotide and a beetle enzyme, successfully identified two potential anticancer compounds.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Telomerase reverse transcriptase (TERT) is crucial for maintaining telomere length and cellular immortality, making it a significant cancer target.
- Despite decades of research, the lack of effective high-throughput screening tools has hindered the development of small molecule telomerase inhibitors for cancer therapy.
Purpose of the Study:
- To develop and validate a novel high-throughput screening (HTS) assay for identifying telomerase inhibitors.
- To utilize a surrogate model system for efficient drug discovery targeting telomerase.
Main Methods:
- A fluorescently coupled HTS assay was developed using a chemically modified reporter nucleotide.
- The Tribolium castaneum telomerase, sharing active site homology with the human enzyme, was employed as a surrogate model.
- A library of approximately 3600 nucleoside mimetics was screened to assess assay performance and identify potential inhibitors.
Main Results:
- The developed assay demonstrated excellent quality and reliability.
- Screening of the nucleoside mimetic library identified two compounds exhibiting telomerase inhibitory activity.
- These inhibitory compounds were further validated through direct enzymatic assays.
Conclusions:
- The novel HTS method offers a promising tool for uncovering new telomerase inhibitors.
- This approach has the potential to advance drug discovery efforts for telomerase-targeted anticancer therapeutics.
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