title: AG2034: a novel inhibitor of glycinamide ribonucleotide formyltransferase.
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.
authors.affiliation: Agouron Pharmaceuticals Inc., San Diego, CA 92121, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Boritzki
authors.forename: C A
authors.initials: CA
authors.lastname: Barlett
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.forename: E F
authors.initials: EF
authors.lastname: Howland
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005493:Folic Acid Antagonists / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology*; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000188:drug therapy; D051026:Phosphoribosylglycinamide Formyltransferase; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D005971:Glutamates; D011743:Pyrimidines; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; D000217:Acyltransferases; C105066:AG 2034