LY 345899 is an inhibitor of methylenetetrahydrofolate dehydrogenase (MTHFD) 1 and MTHFD2, with an IC50 value of 96 and 663nM, respectively [1]. LY 345899 can selectively target cancer cells by inhibiting MTHFD2, interfering with purine synthesis and 1-Carbon metabolism, while not damaging healthy normal cells [2]. LY 345899 has been widely used to inhibit the cyclohydrolase activity of MTHFD1 and induce growth defects in K562 cells[3].
In vitro, LY 345899 treatment (100nM) for 48 hours significantly reduced the number of B cells of the mouse spleen and inhibited the expression and secretion levels of IL-10[4]. Treatment with 10μM LY 345899 for 20 minutes significantly increased the infarct area in the isolated hearts of intact wild-type female mice after ischemia/reperfusion[5].
In vivo, LY 345899 treatment via intraperitoneal injection at a dose of 10mg/kg (5 times a week) for 4 weeks significantly inhibited tumor growth in the SW620 xenograft mouse model, without affecting the body weight of the mice[6].
References:
[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 inhibitor[J]. Cancer research, 2017, 77(4): 937-948.
[2] Tedeschi P M, Vazquez A, Kerrigan J E, et al. Mitochondrial methylenetetrahydrofolate dehydrogenase (MTHFD2) overexpression is associated with tumor cell proliferation and is a novel target for drug development[J]. Molecular Cancer Research, 2015, 13(10): 1361-1366.
[3] Flickinger K M, Wilson K M, Rossiter N J, et al. Conditional lethality profiling reveals anticancer mechanisms of action and drug-nutrient interactions[J]. Science Advances, 2024, 10(40): eadq3591.
[4] Fu Y, Yu B, Wang Q, et al. Oxidative stress-initiated one-carbon metabolism drives the generation of interleukin-10-producing B cells to resolve pneumonia[J]. Cellular & Molecular Immunology, 2024, 21(1): 19-32.
[5] Garbus‐Grant H, Ebenebe‐Kasonde O V, Kabir R, et al. Formate reduces ischemic injury in female hearts lacking alcohol dehydrogenase 5[J]. FASEB BioAdvances, 2025, 7(12): e70075.
[6] 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 implications[J]. JNCI: Journal of the National Cancer Institute, 2019, 111(6): 584-596.