Document Detail

Kinetic characteristics of ICI D1694: a quinazoline antifolate which inhibits thymidylate synthase.
MedLine Citation:
PMID:  1596289     Owner:  NLM     Status:  MEDLINE    
The thymidylate synthase (TS) inhibitor ICI D1694 (N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N -methylamino]-2 - thenoyl)-S-glutamic acid) is a structural analogue of the substrate N5,N10-methylenetetrahydrofolate (5,10-CH2FH4) and is currently under clinical evaluation as a treatment for cancer. The compound is shown here to be a mixed non-competitive inhibitor of TS from murine leukemia (L1210) cells when 5,10-CH2FH4 is varied. This result suggests formation of an inactive complex between TS, 5,10-CH2FH4 and the inhibitor. Thus, binding to only one of the two active sites on the TS homodimer may be sufficient to prevent catalysis fully. Treatment of L1210 cells with ICI D1694 is known to cause intracellular accumulation of the tetraglutamate derivative which is shown here to have a 60-fold higher affinity for TS. The IC50 for inhibition of L1210 cell growth is below the Ki value of ICI D1694 for L1210 TS but above that of the tetraglutamate. The formation of polyglutamates and concentration of drug inside cells, therefore, seem to be responsible for biological activity.
W H Ward; R Kimbell; A L Jackman
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  43     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  1992 May 
Date Detail:
Created Date:  1992-06-26     Completed Date:  1992-06-26     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  2029-31     Citation Subset:  IM    
ICI Pharmaceuticals Mereside, Macclesfield Cheshire, U.K.
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MeSH Terms
Binding Sites
Cell Division / drug effects
Leukemia L1210 / enzymology*
Quinazolines / pharmacology*
Tetrahydrofolates / metabolism
Thiophenes / pharmacology*
Thymidylate Synthase / antagonists & inhibitors*,  isolation & purification
Tumor Cells, Cultured / enzymology
Reg. No./Substance:
0/Quinazolines; 0/Tetrahydrofolates; 0/Thiophenes; 112887-68-0/raltitrexed; 3432-99-3/5,10-methylenetetrahydrofolate; EC Synthase

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