ChemicalBook CAS DataBase List 10538-99-5

10538-99-5

Name	LY 345899)
CAS	10538-99-5
Molecular Formula	C20H21N7O7
MDL Number	MFCD29920315
Molecular Weight	471.42
MOL File	10538-99-5.mol

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

Safety Data

Symbol(GHS)	GHS07
Signal word	Warning
Hazard statements	H302-H312-H332
Precautionary statements	P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P330-P362-P403+P233-P501
WGK Germany	WGK 3
Storage Class	11 - Combustible Solids

Hazard Information

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 .

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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

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