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Tosedostat (CHR2797)

Tosedostat (CHR2797)

Manufacturer	Selleckchem
Category	Oncology Metabolism Diabetes Inhibitors & Compound Libraries Small Molecules By Organ Lung Cancer Bladder Cancer Colorectal Cancer Breast Cancer Heart & Blood Cancer Testicular & Prostate Cancer
Type	Inhibitors
Specific against	other
Amount	10 mg
Item no.	S1522-10
Targets	LAP
CASRN	238750-77-1
eClass 6.1	30220300
eClass 9.0	32160605
Available
Administration	Dosed daily p.o.
Animal Models	Female rats (CBH/cbi) injected i.v. with HOSP.1P cells, male (CBH/cbi) rats injected with HSN LV10 cells, and nude mice (MF1 (nu/nu) inoculated with MDA-MB 435 cells or MDA-MB-468 cells
Cell lines	U-937, HL-60, KG-1, HNT-34 and GDM-1
Chemical Name	(S)-cyclopentyl 2-((R)-2-((S)-1-hydroxy-2-(hydroxyamino)-2-oxoethyl)-4-methylpentanamido)-2-phenylacetate
Clinical Trials	A Phase II study to evaluate the efficacy and safety of CHR-2797 in elderly patients suffering from refractory or relapsed AML has been completed.
Concentrations	Dissolved in DMSO, final concentration ca.1 mM
Description	CHR-2797 is an aminopeptidase inhibitor for LAP, PuSA and Aminopeptidase N with IC50 of 100 nM, 150 nM and 220 nM, respectively.
Dosages	ca.100 mg/kg
Formulation	Dissolved in DMSO and diluted in saline
IC50	100 nM, 100 nM, 100 nM, 100 nM, 100 nM, 100 nM
In vitro	CHR-2797 has almost no effect on Aminopeptidase B, PILSAP, LTA4 hydrolase and MetAP-2 activity with IC50 values of >1 uM, >5 uM, >10 uM and >30 uM, respectively. CHR-2797 is converted into a pharmacologically active acid product (CHR-79888) inside cells, which shows, significant inhibitory activity towards LTA4 hydrolase with IC50 of 8 nM. CHR-2797 exhibits profound anti-proliferative effects against a range of cancer cell lines such as U-937, HL-60, KG-1 and GDM-1 with IC50 values of 10 nM, 30 nM, 15 nM and 15 nM, respectively, but is inactive against HuT 78 and Jurkat E6-1 with IC50 values of >10 uM. There is no obvious correlation between sensitivity to CHR-2797 and the mutational status of p53, PTEN, or K-Ras in cells. CHR-2797 shows selectivity for transformed cells (MrC5-SV2 or K-ras NRK) over non-transformed cells (MrC5 or NRK). CHR-2797 (6 uM) treatment leads to the up-regulation of genes involved in amino acid transport and metabolic pathways, the phosphorylation of eukaryotic initiation factor 2alpha, the inhibition of phosphorylation of mTOR substrates, and reduced protein synthesis in HL-60 cells. [1]
In vivo	Administration of CHR-2797 (ca.100 mg/kg) decreases tumor volumes in vivo, compared to controls, , in a dose-response manner in the rat HOSP.1 lung colonisation model, the rat HSN LV10 chondrosarcoma liver colonisation model, the human MDA-MB-435 breast cancer spontaneous metastasis model, and the human MDA-MB-468 cell xenograft model. [1]
Incubation Time	72 hours
Kinase Assay	Aminopeptidase assays, LAP activity is determined by measuring the hydrolysis of the tripeptide, LGG, which is detected by the derivatization reagent OPA in the presence of beta-mercaptoethanol. The assay is carried out in 96-well assay plates. Wells contain diluted CHR-2797 (5 uL), 10 ug/mL LAP (5 uL) and 40 uL of 0.5 mM LGG. The plate is shaken briefly, and incubated for 90 minutes at 37 C. The reaction is terminated by addition of 200 uL of OPA/beta-Mercaptoethanol per well. The plate is read on the Victor Wallac3 plate reader: excitation, 355nm and emission, 460nm. PuSA activity is determined using the fluorogenic substrate Ala-AMC. Incubation mix contains diluted CHR-2797 (20 uL), substrate (125 uM Ala-AMC in 0.125 M Tris-HCl buffer, pH 7.5, 40 uL) and enzyme (40 uL). After incubation for 2 hours at 37 C, the reaction is stopped by addition of 100 uL 3% (v/v) acetic acid. Fluorescence is measured using a SLT Fluostar fluorimeter. Aminopeptidase N is assayed using the fluorogenic substrate, Ala-AMC. Incubation mix contains diluted CHR-2797 (20 uL), substrate (40 uL, final concentration, 60 uM) and enzyme (40 uL, 1:8000 dilution) and is incubated for 60 minutes at 37 C prior to addition of 100 uL 3% (v/v) acetic acid, to stop the reaction. Fluorescence is measured using a SLT Fluostar fluorimeter.
Method	Cells are exposed to different concentrations of CHR-2797 for 72 hours. During the final 4 hours of this incubation, cells are pulsed with 0.4 uCi/well of [3H]thymidine (specific activity, 5 mCi/mmol), harvested onto GF/C glass fiber filter mats using a Tomtec harvester, and counted on a 1450 MicroBeta scintillation counter to determine the amount of [3H]thymidine incorporated into cellular DNA. Inhibition of the proliferation of human cancer cell lines is measured by [3H]thymidine incorporation.
Molecular Weight (MW)	406, 47
Picture ChemicalStructure Description	Tosedostat (CHR2797) Chemical Structure
Solubility (25C)	DMSO 51 mg/mL, Water <1 mg/mL, Ethanol 5 mg/mL
Storage	2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO

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Amount: 10 mg

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Delivery expected until 7/19/2024