PMID- 16686541
OWN - NLM
STAT- MEDLINE
DCOM- 20060606
LR  - 20211020
IS  - 0022-2623 (Print)
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 49
IP  - 10
DP  - 2006 May 18
TI  - Discovery of a potent, nonpolyglutamatable inhibitor of glycinamide 
      ribonucleotide transformylase.
PG  - 2998-3002
AB  - Glycinamide ribonucleotide transformylase (GAR Tfase) catalyzes the first of two 
      formyl transfer steps in the de novo purine biosynthetic pathway that require 
      folate cofactors. Herein we report the discovery of a potent, 
      nonpolyglutamatable, and selective inhibitor of GAR Tfase. Compound 12, which 
      possesses a tetrazole in place of the gamma-carboxylic acid in the l-glutamate 
      subunit of the potent GAR Tfase inhibitor 1, was active in cellular-based 
      functional assays exhibiting purine-sensitive cytotoxic activity (IC(50) = 40 nM, 
      CCRF-CEM) and was selective for inhibition of rhGAR Tfase (K(i) = 130 nM). 
      Notably, 12 was only 2.5-fold less potent than 1 in cellular assays and 4-fold 
      less potent against rhGAR Tfase. Like 1, this functional activity of 12 in the 
      cell-based assay benefits from and requires transport into the cell by the 
      reduced folate carrier but, unlike 1, is independent of folyl polyglutamate 
      synthase (FPGS) expression levels and polyglutamation.
FAU - DeMartino, Jessica K
AU  - DeMartino JK
AD  - Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps 
      Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, 
      USA.
FAU - Hwang, Inkyu
AU  - Hwang I
FAU - Xu, Lan
AU  - Xu L
FAU - Wilson, Ian A
AU  - Wilson IA
FAU - Boger, Dale L
AU  - Boger DL
LA  - eng
GR  - P01 CA063536/CA/NCI NIH HHS/United States
GR  - P01 CA063536-06/CA/NCI NIH HHS/United States
GR  - P01 CA063536-09/CA/NCI NIH HHS/United States
GR  - CA63536/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (10-(trifluoroacetyl)-5,10-dideazaacyclic-5,6,7,8-tetrahydrofolic acid)
RN  - 0 
      (2-(4-(6-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-1,1,1-trifluoro-2-oxohexan-3-yl)benzamido)-4-(1H-tetrazol-5-yl)butanoic 
      acid)
RN  - 0 (Aminobutyrates)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Pyrimidinones)
RN  - 0 (Tetrahydrofolates)
RN  - 0 (Tetrazoles)
RN  - 25513-46-6 (Polyglutamic Acid)
RN  - EC 2.1.2.2 (Phosphoribosylglycinamide Formyltransferase)
RN  - EC 6.3.2.- (Peptide Synthases)
RN  - EC 6.3.2.17 (folylpolyglutamate synthetase)
SB  - IM
MH  - Aminobutyrates/*chemical synthesis/chemistry/pharmacology
MH  - Antineoplastic Agents/*chemical synthesis/chemistry/pharmacology
MH  - Cell Line, Tumor
MH  - Drug Screening Assays, Antitumor
MH  - Humans
MH  - Peptide Synthases/metabolism
MH  - Phosphoribosylglycinamide Formyltransferase/*antagonists & inhibitors/chemistry
MH  - Polyglutamic Acid/metabolism
MH  - Pyrimidinones/*chemical synthesis/chemistry/pharmacology
MH  - Structure-Activity Relationship
MH  - Substrate Specificity
MH  - Tetrahydrofolates/chemistry
MH  - Tetrazoles/*chemical synthesis/chemistry/pharmacology
PMC - PMC2531195
MID - NIHMS61054
EDAT- 2006/05/12 09:00
MHDA- 2006/06/07 09:00
PMCR- 2008/09/06
CRDT- 2006/05/12 09:00
PHST- 2006/05/12 09:00 [pubmed]
PHST- 2006/06/07 09:00 [medline]
PHST- 2006/05/12 09:00 [entrez]
PHST- 2008/09/06 00:00 [pmc-release]
AID - 10.1021/jm0601147 [doi]
PST - ppublish
SO  - J Med Chem. 2006 May 18;49(10):2998-3002. doi: 10.1021/jm0601147.