An MTHFD inhibitor
LY345899 is an inhibitor of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and MTHFD2 (IC50s = 96 and 663 nM, respectively).1 It decreases the NADPH-to-NADP+ (NADPH/NADP+) and reduced glutathione-to-oxidized glutathione (GSH/GSSG) ratios and increases the production of reactive oxygen species (ROS) in HCT116, SW620, and LoVo colorectal cancer cells when used at a concentration of 10 ?M.2 LY345899 is cytotoxic to SW620 and LoVo cells, an effect that can be reversed by the antioxidant N-acetyl-L-cysteine . In vivo, LY345899 (10 mg/kg) reduces tumor growth in a patient-derived xenograft (PDX) mouse model of colorectal cancer.
1.Gustafsson, R., Jemth, A.-S., Gustafsson, N.M.S., et al.Crystal structure of the emerging cancer target MTHFD2 in complex with a substrate-based inhibitorCancer Res.77(4)937-948(2017) 2.Ju, H.-Q., Lu, Y.-X., Chen, D.-L., et al.Modulation of redox homeostasis by inhibition of MTHFD2 in colorectal cancer: Mechanisms and therapeutic implicationsJ. Natl. Cancer Inst.111(6)584-596(2109)
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