The antifolates: Evolution, new agents in the clinic, and how targeting delivery via specific membrane transporters is driving the development of a next generation of folate analogs

I. David Goldman, Shrikanta Chattopadhyay, Rongbao Zhao, Richard Moran

Research output: Contribution to journalReview article

50 Scopus citations


More than 50 years after the introduction of the dihydrofolate reductase inhibitor, methotrexate, new antifolates have emerged and have been incorporated into the chemotherapeutic armamentarium. These include pralatrexate, with the same target as methotrexate, but with enhanced properties, and pemetrexed, with different enzyme targets and properties. Current synthetic efforts are focused on developing antifolates that are selectively delivered to cancer cells, but not to normal proliferating cells, exploiting the different properties of folate transporters. In another novel approach, drugs structurally and mechanistically unrelated to folates are linked to and use folic acid as a carrier to be endocytosed by folate receptors and then released to inhibit their cellular targets. This review describes the evolution and current status of antifolate pharmacology and prospects for the development of the next generation of folate analogs.

Original languageEnglish (US)
Pages (from-to)1409-1423
Number of pages15
JournalCurrent Opinion in Investigational Drugs
Issue number12
Publication statusPublished - Dec 1 2010



  • Aminopterin
  • PCFT
  • RFC
  • SLC19A1
  • SLC46A1
  • antifolate
  • folate
  • folate receptor
  • methotrexate
  • pemetrexed
  • pralatrexate
  • proton-coupled folate transporter
  • reduced folate carrier

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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