title: Inhibitors of de novo nucleotide biosynthesis as drugs.
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.
authors.affiliation: School of Molecular and Microbial Biosciences, University of Sydney, Sydney, NSW, 2006, Australia. ric@mmb.usyb.edu.au
authors.forename: Richard I
authors.initials: RI
authors.lastname: Christopherson
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Lyons
authors.forename: Paul K
authors.initials: PK
authors.lastname: Wilson
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D009711:Nucleotides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D011685:Purine Nucleotides / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011742:Pyrimidine Nucleotides / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D004791:Enzyme Inhibitors; D009711:Nucleotides; D011685:Purine Nucleotides; D011742:Pyrimidine Nucleotides