title: 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.
abstract: 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.
authors.affiliation: Albert Einstein College of Medicine Cancer Center, Departments of Medicine and Molecular Pharmacology, Chanin Two, 1300 Morris Park Avenue, Bronx, NY 10803, USA. i.david.goldman@einstein.yu.edu
authors.forename: I David
authors.initials: ID
authors.lastname: Goldman
authors.forename: Shrikanta
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: Rongbao
authors.initials: R
authors.lastname: Zhao
authors.forename: Richard
authors.initials: R
authors.lastname: Moran
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D004337:Drug Carriers; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000378:metabolism / Q000494:pharmacology*; D058972:Folic Acid Transporters / Q000378:metabolism*; D006801:Humans; D010455:Peptides / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D005493:Folic Acid Antagonists; D058972:Folic Acid Transporters; D010455:Peptides; C097188:polyglutamine; D005492:Folic Acid