Identification of fumarate hydratase inhibitors with nutrient-dependent cytotoxicity.

ABSTRACT: Development of cell-permeable small molecules that target enzymes involved in energy metabolism remains important yet challenging. We describe here the discovery of a new class of compounds with a nutrient-dependent cytotoxicity profile that arises from pharmacological inhibition of fumarate hydratase (also known as fumarase). This finding was enabled by a high-throughput screen of a diverse chemical library in a panel of human cancer cell lines cultured under different growth conditions, followed by subsequent structure-activity optimization and target identification. While the highest cytotoxicity was observed under low glucose concentrations, the antiproliferative activities and inhibition of oxygen consumption rates in cells were distinctly different from those displayed by typical inh

SUBMITTER: Takeuchi T 

PROVIDER: S-EPMC4308746 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature