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Acc Chem Res. 2002 Nov;35(11):961-71.

Inhibitors of de novo nucleotide biosynthesis as drugs.

Author information

1
School of Molecular and Microbial Biosciences, University of Sydney, Sydney, NSW, 2006, Australia. ric@mmb.usyb.edu.au

Abstract

Potent inhibitors of enzymes catalyzing reactions in the de novo pathways for biosynthesis of purine and pyrimidine nucleotides are synthetic or natural-product analogues of pathway intermediates or, more recently, inhibitors rationally designed from a knowledge of the catalytic mechanism. Such inhibitors may be effective drugs against cancer, inflammatory disorders, or various infections. For human cancer, the purine pathway may be a better target for inhibition than the pyrimidine pathway, where toxic side effects are more apparent. Drugs such as methotrexate and 6-mercaptopurine have multiple sites of action, making it difficult to quantitatively predict their effects upon cells. Rational design of inhibitors based upon the X-ray structure of the target enzyme has the prospect of yielding drugs with only one site of action in human cells. Such a drug is VX-497, a potent inhibitor of the purine enzyme, IMP dehydrogenase.

PMID:
12437321
[Indexed for MEDLINE]

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