LY345899 (LY354899) is a methylenetetrahydrofolate dehydrogenase inhibitor (MTHFD1 IC50 = 96 nM with 30 μM folitixorin and 400 μM NADP+; MTHFD2 IC50 = 663 nM with 5 μM folitixorin and 250 μM NAD+) that exerts antiproliferation activity against cancer cells by targeting the folate cycle. Co-administer LY345899 with the dihydrofolate reductase (DHFR) inhibitor methotrexate (MTX) overcomes AML MTX resistance (50 mg/kg) in mice in vivo (10 mg/kg q.o.d. i.p.).
Methylenetetrahydrofolate dehydrogenase 1/2 (MTHFD1/2) inhibitor that exerts anti-cancer efficacy in vitro and in vivo by targeting the folate cycle.
The Journal of pharmacology and experimental therapeutics, 287(1), 315-321 (1998-10-09)
5,6,7,8-Tetrahydro-N5,N10-carbonylfolic acid (LY354899) has been demonstrated to inhibit the dehydrogenase activity of C1-tetrahydrofolate synthase. This compound was only moderately antiproliferative toward CCRF-CEM lymphocytic leukemia cells in culture, but induced apoptosis after long incubation times. Slightly greater potency was observed in
Metabolic reprogramming by oncogenic signaling is a hallmark of cancer. Hyperactivation of Wnt/β-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the mechanisms inducing hyperactivation of Wnt/β-catenin signaling and strategies for targeting this pathway are incompletely understood. In this
The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in
Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor.
Journal of the National Cancer Institute, 111(6), 584-596 (2018-12-12)
Overcoming oxidative stress is a critical step for tumor progression; however, the underlying mechanisms in colorectal cancer (CRC) remain unclear. We investigated nicotinamide adenine dinucleotide (phosphate) (NAD(P))-dependent enzyme methylene tetrahydrofolate dehydrogenase 2 (MTHFD2) expression, clinical relevance, redox modification, and molecular
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