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Antifolates are folic acid analogs that block the enzymes of folate-dependent nucleotide synthesis. Reduced folates carry one-carbon units for the synthesis of thymidylate and purines. Antifolates compete with these cofactors at dihydrofolate reductase (DHFR), thymidylate synthase (TS) or glycinamide ribonucleotide formyltransferase (GARFT). Depleted nucleotide pools then stall DNA replication in dividing cells. Methotrexate disodium and pralatrexate inhibit DHFR, while pemetrexed acts on DHFR, TS and GARFT. Nolatrexed Dihydrochloride is a lipophilic TS inhibitor, pelitrexol targets GARFT, and LSN 3213128 inhibits aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT). The set also includes reduced folates such as Levoleucovorin Calcium and Calcium N5-methyltetrahydrofolate, which supply folate in culture or bypass DHFR inhibition.
