Folylpolyglutamate synthetase as a target for therapeutic intervention

The antifolate methotrexate (MTX). which targets the folate-dependent enzyme dihydrofolate reductase (DHFR), has been used effectively in cancer chemotherapy for over 50 years. Extensive efforts have been mounted to develop DHFR inhibitors that are more selective and/or have a wider tumor range than MTX and to develop inhibitors of other folate-dependent enzymes, principally thymidylate synthase and the enzymes of de novo purine synthesis. To date, these efforts have met with limited success. Another potential pathway for exploitation is the synthesis of polyly-glutamyl) forms of reduced folates. Folylpolyglutamates are essential for folate-medlated one-carbon metaboiism to function and hence are essential for cell survival. Thus, folylpolyglutamate synthetase (FPGS), which is responsible for synthesis of these metabolites, is suggested as a target for drug development. This article reviews the rationale for synthesis of FPGS inhibitors and the progress to date in developing potent, cell-permeable inhibitors of this critical enzyme.