MTHFD2 is a mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase involved in one-carbon metabolism. It is responsible for the oxidation of methylene-THF to 10-formyl-THF in mitochondria, which is highly overexpressed in cancer cells and embryonic cells. LY345899, a Folate analog, is a MTHFD inbhibitor with IC50 values of 96 nM and 663 nM for MTHFD1 and MTHFD2, respectively[1]. LY345899 treatment for 72 hours caused a decrease in the cell viability of the CRC cells with highly expressed MTHFD2 (LoVo, SW620, HCT116). LY345899 (1 μM; 14 days) significantly reduced cell colony formation among these CRC cells. Further, LY345899 treatment decreased cellular NADPH/NADP+ and GSH/GSSG levels. Accordingly, LY345899 treatment for 48 hours obviously enhanced cell death under hypoxia or detached conditions. In SW620-based xenograft mice, LY345899 (5 mg/kg or 10 mg/kg; i.p.; 5 d/wk) showed potent antitumor activity in vivo, which was evident by the reduced SW620 cell or PDX-based tumor growth and tumor weight[2].
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