High-Throughput Screening Tool to Identify Small Molecule Inhibitors of Telomerase.

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.