PMID: 8958185Jan 1, 1996Paper

AG2034: a novel inhibitor of glycinamide ribonucleotide formyltransferase

Investigational New Drugs
T J BoritzkiE J Howland

Abstract

The glycinamide ribonucleotide formyltransferase (GARFT) inhibitor, 4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-6] [1,4]thiazin-6-yl)-(S)-ethyl]-2,5-thienoyl-L-glutamic acid (AG2034), was designed from the X-ray structure of the GARFT domain of the human tri functional enzyme. AG2034 inhibits human GARFT (Ki = 28 nM), has a high affinity for the folate receptor (Kd = 0.0042 nM), and is a substrate for rat liver folylpolyglutamate synthetase (K(m) = 6.4 microM, Vmax = 0.48 nmole/hr/mg). The IC50 for growth inhibition was 4 nM against L1210 cells and 2.9 nM for CCRF-CEM cells in culture. In vitro growth inhibition can be reversed by addition of either hypoxanthine or AICA (5-aminoimidazole-4-carboxamide) to the culture medium. A cell line with impaired transport of reduced folates, L1210/C1920, was resistant to AG2034 indicating that this compound can enter cells by utilizing the reduced folate carrier. AG2034 showed in vivo antitumor activity against the 6C3HED, C3HBA, and B-16 murine tumors and in the HxGC3, KM20L2, LX-1, and H460 human xenograft models, and has been selected for preclinical development towards clinical trials.

References

Jul 1, 1992·Proceedings of the National Academy of Sciences of the United States of America·R J AlmassyZ Hostomska
Feb 3, 1986·European Journal of Biochemistry·G MatlashewskiL Crawford
Aug 1, 1984·Analytical Biochemistry·R G Moran, P D Colman

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Citations

Oct 6, 1999·Current Opinion in Immunology·K D BagshaweR J Knox
Aug 9, 2008·Journal of Medicinal Chemistry·Jessica K DeMartinoDale L Boger
Aug 28, 2012·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Nitzan Gonen, Yehuda G Assaraf
Nov 10, 2006·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·G Jansen, R Pieters
Aug 31, 2013·Scandinavian Journal of Rheumatology·J W van der HeijdenG Jansen
Sep 8, 2012·Cancer Biology & Therapy·Sita Kugel DesmoulinLarry H Matherly
Nov 30, 1999·Archives of Biochemistry and Biophysics·V D AntleC A Carperelli
Oct 25, 2003·Oncogene·Rongbao Zhao, I David Goldman
Oct 1, 2003·The Journal of Biological Chemistry·Julie L Bronder, Richard G Moran
May 12, 2012·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Shouxin ZhouZhili Zhang
Jan 8, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Larry H MatherlyZhanjun Hou
Feb 20, 2007·Molecular Cancer Therapeutics·Shrikanta ChattopadhyayI David Goldman
Nov 17, 2019·Cancer Letters·Alyncia D RobinsonSooryanarayana Varambally
Apr 17, 2021·ACS Pharmacology & Translational Science·Christine R CuthbertsonNouri Neamati

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