Open AccessGlutamine Antagonist GA-607 Causes a Dramatic Accumulation of FGAR which can be used to Monitor Target Engagement
Author(s) -
Jesse Alt,
Sadakatali S. Gori,
Kathryn M. Lemberg,
Arindom Pal,
Vijayabhaskar Veeravalli,
Ying Wu,
Joanna Marie H. Aguilar,
Ranjeet Prasad Dash,
Lukáš Tenora,
Pavel Majer,
Qi Sun,
Barbara S. Slusher,
Rana Rais
Publication year - 2021
Publication title -
current drug metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.667
H-Index - 106
eISSN - 1875-5453
pISSN - 1389-2002
DOI - 10.2174/1389200222666210831125041
Subject(s) - chemistry , purine metabolism , prodrug , inosine , glutamine , pharmacokinetics , pharmacology , enzyme , cancer research , biochemistry , biology , amino acid
Metabolomic analyses from our group and others have shown that tumors treated with glutamine antagonists (GA) exhibit robust accumulation of formylglycinamide ribonucleotide (FGAR), an intermediate in the de novo purine synthesis pathway. The increase in FGAR is attributed to the inhibition of the enzyme FGAR amidotransferase (FGAR-AT) that catalyzes the ATP-dependent amidation of FGAR to formylglycinamidine ribonucleotide (FGAM). While perturbation of this pathway resulting from GA therapy has long been recognized, no study has reported systematic quantitation and analyses of FGAR in plasma and tumors.