Inhibitors of de novo nucleotide biosynthesis as drugs.
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.
Christopherson
Richard I
RI
School of Molecular and Microbial Biosciences, University of Sydney, Sydney, NSW, 2006, Australia. ric@mmb.usyb.edu.au
Lyons
Stephen D
SD
Wilson
Paul K
PK
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
D004791:Enzyme Inhibitors; D009711:Nucleotides; D011685:Purine Nucleotides; D011742:Pyrimidine Nucleotides