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Pralatrexate is an inhibitor of DHFR with Ki value of 45 nM [1].

Dihydrofolate reductase (DHFR) is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, a methyl group shuttle required for the synthesis of purines, thymidylic acid, and certain amino acids.

Pralatrexate is a DHFR inhibitor with high affinity for folylpolyglutamate synthetase (FPGS) and reduced folate carrier 1 (RFC-1), resulting in extensive internalization and accumulation in tumour cells. In 15 human cancer cell lines, pralatrexate showed antiproliferative effects with IC50 < 0.1 μM in PC3, SCC61, DU145, HT29, HOP62, SQ20B, HOP92, HEP2 and IGROV1 cells. While it showed antiproliferative effects with IC50≥ 9 μM in Colo205, HCC2998, MCF7, HCT116, OVCAR3 and MDA-MB-435 cells [2].

In MV522 human non-small cell lung cancer (NSCLC) xenograft, pralatrexate showed increased antitumor activity. In the 2 mg/kg pralatrexate-treated group, the 38% tumor growth inhibition (TGI) was observed. In NCI-H460 NSCLC xenograft, pralatrexate showed antitumor activity in a dose-dependent way. TGI of 1 mg/kg and 2 mg/kg pralatrexate-treated groups was 34% and 52%, respectively. In the two xenografts, pralatrexate resulted in weight loss, which suggested its toxicity [1].

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