Wong Lai Hong, Unciti-Broceta Asier, Spitzer Michaela, White Rachel, Tyers Mike, Harrington Lea
Wellcome Trust Centre for Cell Biology, King's Buildings, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JR, UK.
Chem Biol. 2013 Mar 21;20(3):333-40. doi: 10.1016/j.chembiol.2012.12.008.
Telomerase comprises a reverse transcriptase and an internal RNA template that maintains telomeres in many eukaryotes, and it is a well-validated cancer target. However, there is a dearth of small molecules with efficacy against human telomerase in vivo. We developed a surrogate yeast high-throughput assay to identify human telomerase inhibitors. The reversibility of growth arrest induced by active human telomerase was assessed against a library of 678 compounds preselected for bioactivity in S. cerevisiae. Four of eight compounds identified reproducibly restored growth to strains expressing active human telomerase, and three of these four compounds also specifically inhibited purified human telomerase in vitro. These compounds represent probes for human telomerase function, and potential entry points for development of lead compounds against telomerase-positive cancers.
端粒酶由逆转录酶和内部RNA模板组成，在许多真核生物中维持端粒，是一个经过充分验证的癌症靶点。然而，缺乏在体内对人端粒酶有效的小分子。我们开发了一种替代酵母高通量测定法来鉴定人端粒酶抑制剂。针对在酿酒酵母中预先选择具有生物活性的678种化合物库，评估了活性人端粒酶诱导的生长停滞的可逆性。可重复鉴定出的八种化合物中的四种使表达活性人端粒酶的菌株恢复生长，这四种化合物中的三种在体外也能特异性抑制纯化的人端粒酶。这些化合物代表了人端粒酶功能的探针，以及开发针对端粒酶阳性癌症的先导化合物的潜在切入点。
