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Multiple folate enzyme inhibition: mechanism of a novel pyrrolopyrimidine-based antifolate LY231514 (MTA)

Authors:	Chuan Shih Lillian L Habeck Laurane G Mendelsohn Victor J Chen Richard M Schultz

Institution:	^aLilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285,USA

Abstract:

Keywords:	Abbreviations: r recombinant h human m murine TS thymidylate synthase DHFR dihydrofolate reductase GARFT glycinamide ribonucleotide formyltransferase AICARFT aminoimidazole carboxamide ribonucleotide formyltransferase (EC 2 1 2 3) C1-S C1 tetrahydrofolate synthase D/C the protein domain of C1-S containing the 5 10-methylenetetrahydrofolate dehydrogenase (EC 1 5 1 5) and 5 10-methenyltetrahydrofolate cyclohydrolase activities D/C/S the full length enzyme of C1-S containing 5 10-methylenetetrahydrofolate dehydrogenase 5 10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activities (EC 6 3 4 3) FPGS folylpolyglutamate synthetase HEPES N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid] MTT 3-[4 5-dimethylthiazol-2yl]-2 5-diphenyltetrazolium bromide DDATHF 5 10-dideazatetrahydrofolic acid Lometrexol 6R-DDATHF ME mercaptoethanol NADPH β-nicotinamide adenine dinucleotide phosphate reduced form ATP adenosine 5′-triphosphate 6R-MTHF 6[R]-5 10-methylene-5 6 7 8-tetrahydrofolate LY231514 N-[4-[2-(2-amino-3 4-dihydro-4-oxo-7H-pyrrolo[2 3-d]pyrimidin-5-yl)ethyl]-benzoyl]-L-glutamic acid MTA multitargeted antifolate
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