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| | LY 345899) Basic information |
| Product Name: | LY 345899) | | Synonyms: | LY 345899);LY-345899
(LY345899;L-Glutamic acid, N-[4-(3-amino-1,2,5,6,6a,7-hexahydro-1,9-dioxoimidazo[1,5-f]pteridin-8(9H)-yl)benzoyl]-;(2S)-2-(4-(3-Amino-1,9-dioxo-1,2,5,6,6a,7-hexahydroimidazo[1,5-f]pteridin-8(9H)-yl)benzamido)pentanedioic acid;inhibit,LY345899,LY-345899,Inhibitor,LY 345899,Methylenetetrahydrofolate Dehydrogenase (MTHFD);(2S)-2-[(4-{3-amino-1,9-dioxo-1H,4H,5H,6H,6aH,7H,8H,9H-imidazo[1,5-f]pteridin-8-yl}phenyl)formamido]pentanedioic acid;LY 345899, 10 mM in DMSO | | CAS: | 10538-99-5 | | MF: | C20H21N7O7 | | MW: | 471.42 | | EINECS: | | | Product Categories: | | | Mol File: | 10538-99-5.mol |  |
| | LY 345899) Chemical Properties |
| density | 1.82±0.1 g/cm3(Predicted) | | storage temp. | Store at -20°C | | solubility | DMSO:125.0(Max Conc. mg/mL);265.16(Max Conc. mM) | | form | A solid | | pka | 3.46±0.10(Predicted) | | color | Light yellow to yellow | | SMILES | O=C1N2C3=C(NC(N)=NC3=O)NCC2CN1C4=CC=C(C=C4)C(N[C@H](C(O)=O)CCC(O)=O)=O |
| WGK Germany | WGK 3 | | Storage Class | 11 - Combustible Solids |
| | LY 345899) Usage And Synthesis |
| Uses | LY 345899 is a Folate analog and is a methylene tetrahydrofolate dehydrogenase (MTHFD1; DC301) and MTHFD2 inbhibitor with IC50 values of 96 nM and 663 nM, respectively and a Ki of 18 nM for MTHFD1[1][2][3]. | | Biological Activity | LY 345899, a folate analog, is also a methylenetetrahydrofolate dehydrogenase (MTHFD1; DC301) and MTHFD2 inhibitor with IC50 values of 96 nM and 663 nM, respectively, and Ki value for MTHFD1 of 18 nM. | | in vitro | LY 345899 could suppress the MTHFD enzyme in the cytoplasm and mitochondria.
LY 345899 could disturb the NADPH and redox homeostases and accelerate cell death under oxidative stress, such as hypoxia, or causing in vitro anchorage independence and in vivo impaired tumor growth and metastasis. | | in vivo | LY345899 (Intraperitoneal injection; 5-10 mg/kg; 5 d/wk; 4 weeks) shows potent antitumor activity and displays therapeutic activity against CRC in vivo . < td class="col1 fwb"> Animal Model: | SW620 or PDX-based BABL/c nude colorectal cancer (CRC) model | < td class="col1 fwb"> Dosage: | 5-10 mg/kg | | Administration: | Intraperitoneal injection; 5-10 mg/kg; 5 d/wk; 4 weeks | | Result : | Displayed lower cell proliferation indices and higher cell apoptosis. Exhibited no statistically significant weight loss or other signs of acute or delayed toxicity in mice. | table> | target | Ki: 18 nM (MTHFD1); IC50: 96 nM (MTHFD1) and 663 nM (MTHFD2) | | References | [1] Schmidt A, et al. Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase. Biochemistry. 2000 May 30;39(21):6325-35. DOI:10.1021/bi992734y
[2] Tedeschi PM, et al. Mitochondrial Methylenetetrahydrofolate Dehydrogenase (MTHFD2) Overexpression Is Associated with Tumor Cell Proliferation and Is a Novel Target for Drug Development. Mol Cancer Res. 2015 Oct;13(10):1361-6. DOI:10.1158/1541-7786.MCR-15-0117
[3] Gustafsson R, et al. Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor. Cancer Res. 2017 Feb 15;77(4):937-948. DOI:10.1158/0008-5472.CAN-16-1476
[4] Huai-Qiang Ju, et al.Modulation of Redox Homeostasis by Inhibition of MTHFD2 in Colorectal Cancer: Mechanisms and Therapeutic Implications. J Natl Cancer Inst. 2019 Jun 1;111(6):584-596. DOI:10.1093/jnci/djy160 |
| | LY 345899) Preparation Products And Raw materials |
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Tag:LY 345899)(10538-99-5)
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