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Glutamine Antagonist GA-607 Causes a Dramatic Accumulation of FGAR which can be used to Monitor Target Engagement
J. Alt, SS. Gori, KM. Lemberg, A. Pal, V. Veeravalli, Y. Wu, JMH. Aguilar, RP. Dash, L. Tenora, P. Majer, Q. Sun, BS. Slusher, R. Rais
Jazyk angličtina Země Nizozemsko
Typ dokumentu časopisecké články
Grantová podpora
R01 CA193895
NCI NIH HHS - United States
R01CA193895R, R01CA229451
NIH Grant
T32 CA060441
NCI NIH HHS - United States
R01 CA229451
NCI NIH HHS - United States
RVO 61388963
Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic-CureSearch Young Investigator Award
LTAUSA18166
Bloomberg Kimmel Institute for Cancer Immunotherapy-Ministry of Education, Youth and Sports of the Czech Republic (Program INTER-EXCELLENCE)
- MeSH
- biomarkery farmakologické analýza metabolismus MeSH
- chromatografie kapalinová metody MeSH
- glutamin antagonisté a inhibitory MeSH
- glycin analogy a deriváty analýza metabolismus MeSH
- hmotnostní spektrometrie metody MeSH
- metabolické sítě a dráhy účinky léků MeSH
- myši MeSH
- nádorové biomarkery analýza metabolismus MeSH
- nádory * farmakoterapie metabolismus MeSH
- ribonukleotidy * analýza metabolismus MeSH
- vyvíjení léků metody MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: 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. OBJECTIVE: Herein, we aimed to evaluate the efficacy of our recently discovered tumor-targeted GA prodrug, GA-607 (isopropyl 2-(6-acetamido-2-(adamantane-1-carboxamido)hexanamido)-6-diazo-5-oxohexanoate), and demonstrate its target engagement by quantification of FGAR in plasma and tumors. METHODS: Efficacy and pharmacokinetics of GA-607 were evaluated in a murine EL4 lymphoma model followed by global tumor metabolomic analysis. Liquid chromatography-mass spectrometry (LC-MS) based methods employing the ion-pair chromatography approach were developed and utilized for quantitative FGAR analyses in plasma and tumors. RESULTS: GA-607 showed preferential tumor distribution and robust single-agent efficacy in a murine EL4 lymphoma model. While several metabolic pathways were perturbed by GA-607 treatment, FGAR showed the highest increase qualitatively. Using our newly developed sensitive and selective LC-MS method, we showed a robust >80- and >10- fold increase in tumor and plasma FGAR levels, respectively, with GA-607 treatment. CONCLUSION: These studies describe the importance of FGAR quantification following GA therapy in cancer and underscore its importance as a valuable pharmacodynamic marker in the preclinical and clinical development of GA therapies.
Drug Metabolism Covance Laboratories Inc Madison WI 53704 United States
Jiangxi Science and Technology Normal University Nanchang Jiangxi 330013 China
Johns Hopkins Drug Discovery Johns Hopkins School of Medicine Baltimore MD 21205 United States
Citace poskytuje Crossref.org
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