Chemical genomics screening of drugs modulating functions of telomere/telomerase

点击翻译按钮获取中文摘要

In order to discover new telomerase inhibitors or new agents that act on telomere regulation mechanism which does not based on telomerase inhibition, we developed an unprecedented unique screening method with induction of shortened telomere as an activity indicator by a forward chemical approach using a yeast strain with shortened telomere length and found antimicrobial, anticancer compounds USC 1025A and chrolactomycin (TEY7) produced by microorganisms as active compounds. It was revealed that these compounds possess telomere-shortening-inducing activity as well as telomerase inhibitory activity within tumor cells but neither detailed mechanism of action nor direct target molecules are still unknown.The objectives of the study is to elucidate the mechanism of action of these compounds on the molecular level by identifying intracellular target molecules to which the compounds bind directly and to validate the possibility of the identified molecules as new molecular targets of anticancer agents by analyzing the function of the identified target molecules in telomere regulation and cancerous change of cells.In the study, we used biotin-labeled probes of UCS1025A and TEY7 and found the protein that binds to respective compound. As these labeled proteins are thought to contain a direct active site of the compounds, we made an analysis by in-gel protease digestion and mass spectrometry to identify binding protein.It can be expected that identification of the target molecules of these compounds and elucidation of their mechanisms of action will provide a new drug discovery approach that leads to development of new anticancer agents acting specifically on cancer cells with much less side effects compared to existing anticancer drugs.