Inhibitors of de novo nucleotide biosynthesis as drugs

Acc Chem Res. 2002 Nov;35(11):961-71. doi: 10.1021/ar0000509.


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.

Publication types

  • Review

MeSH terms

  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Nucleotides / antagonists & inhibitors*
  • Nucleotides / biosynthesis*
  • Purine Nucleotides / antagonists & inhibitors
  • Purine Nucleotides / biosynthesis
  • Pyrimidine Nucleotides / antagonists & inhibitors
  • Pyrimidine Nucleotides / biosynthesis


  • Enzyme Inhibitors
  • Nucleotides
  • Purine Nucleotides
  • Pyrimidine Nucleotides