title: Discovery of a potent, nonpolyglutamatable inhibitor of glycinamide ribonucleotide transformylase.
abstract: Glycinamide ribonucleotide transformylase (GAR Tfase) catalyzes the first of two formyl transfer steps in the de novo purine biosynthetic pathway that require folate cofactors. Herein we report the discovery of a potent, nonpolyglutamatable, and selective inhibitor of GAR Tfase. Compound 12, which possesses a tetrazole in place of the gamma-carboxylic acid in the l-glutamate subunit of the potent GAR Tfase inhibitor 1, was active in cellular-based functional assays exhibiting purine-sensitive cytotoxic activity (IC(50) = 40 nM, CCRF-CEM) and was selective for inhibition of rhGAR Tfase (K(i) = 130 nM). Notably, 12 was only 2.5-fold less potent than 1 in cellular assays and 4-fold less potent against rhGAR Tfase. Like 1, this functional activity of 12 in the cell-based assay benefits from and requires transport into the cell by the reduced folate carrier but, unlike 1, is independent of folyl polyglutamate synthase (FPGS) expression levels and polyglutamation.
authors: Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors: Jessica K
authors: JK
authors: DeMartino
authors: Inkyu
authors: I
authors: Hwang
authors: Lan
authors: L
authors: Xu
authors: Ian A
authors: IA
authors: Wilson
authors: Dale L
authors: DL
authors: Boger