A yeast chemical genetic screen identifies inhibitors of human telomerase

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Telomerase is crucial for telomere maintenance in eukaryotes and a validated cancer target.
• A significant gap exists in identifying effective in vivo small molecule inhibitors for human telomerase.

Purpose of the Study:

• To develop and utilize a surrogate yeast high-throughput assay for identifying novel human telomerase inhibitors.
• To screen a preselected library of bioactive compounds for their ability to inhibit human telomerase.

Main Methods:

• A high-throughput screening assay was established in Saccharomyces cerevisiae (yeast) to identify compounds affecting human telomerase activity.
• A library of 678 preselected bioactive compounds was screened for their ability to reverse growth arrest induced by active human telomerase.
• In vitro assays were used to confirm the inhibitory activity of identified compounds against purified human telomerase.

Main Results:

• Eight compounds reproducibly restored growth in yeast strains expressing active human telomerase.
• Three of these four compounds demonstrated specific inhibition of purified human telomerase in vitro.
• These findings validate the yeast assay as a tool for discovering telomerase inhibitors.

Conclusions:

• The identified compounds serve as valuable probes for studying human telomerase function.
• These compounds represent promising starting points for the development of novel therapeutic agents targeting telomerase-positive cancers.