Discovery of a potent, nonpolyglutamatable inhibitor of glycinamide ribonucleotide transformylase.

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DeMartino JK, Hwang I, Xu L, Wilson IA, Boger DL

Discovery of a potent, nonpolyglutamatable inhibitor of glycinamide ribonucleotide transformylase.

J Med Chem. 2006 May 18;49(10):2998-3002.

PubMed ID

16686541 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Glutamic acid	Folylpolyglutamate synthase, mitochondrial	Protein	Humans	Unknown	Not Available	Details