AG2034: a novel inhibitor of glycinamide ribonucleotide formyltransferase.
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| 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.
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| Authors | T J Boritzki, C A Barlett, C Zhang, E F Howland |
| Journal | Investigational new drugs (Invest New Drugs) Vol. 14 Issue 3 Pg. 295-303 ( 1996) ISSN: 0167-6997 [Print] United States |
| PMID | 8958185 (Publication Type: Journal Article) |
| Chemical References |
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