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Pemetrexed is pyrrotopyrimidine-based, multi-targeted antifolate with broad in vivo antitumor activity. Originally identified as a highly efficient substrate for folylpolyglutamate synthase, pemetrexed potently inhibits multiple folate-dependent enzymes involved in both purine and pyrimidine synthesis including thymidylate synthase (Ki = 109 nM), dihydrofolate reductase (Ki = 7 nM), glycinamide ribonucleotide formyltransferase (Ki = 9.3 μM), and aminoimidazole carboxamide ribonucleotide formyltransferase (Ki = 3.6 μM). Its antiproliferative activity has been demonstrated in a wide variety of solid tumors, including non-small cell lung, breast, mesothelioma, colorectal, pancreatic, gastric, bladder, cervix, and head and neck.

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