Tosedostat (CHR2797)

Catalog No.S1522 2 Product Citations

Tosedostat (CHR2797) is an aminopeptidase inhibitor for LAP, PuSA and Aminopeptidase N with IC50 of 100 nM, 150 nM and 220 nM, respectively, and does not effectively inhibit either PILSAP, MetAP-2, LTA4 hydrolase, or MetAP-2. Phase 2.

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USD 470 In stock
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Tosedostat (CHR2797) Chemical Structure

Tosedostat (CHR2797) Chemical Structure
Molecular Weight: 406.47

Validation & Quality Control

Quality Control & MSDS

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Product Information

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Product Description

Biological Activity

Description Tosedostat (CHR2797) is an aminopeptidase inhibitor for LAP, PuSA and Aminopeptidase N with IC50 of 100 nM, 150 nM and 220 nM, respectively, and does not effectively inhibit either PILSAP, MetAP-2, LTA4 hydrolase, or MetAP-2. Phase 2.
Targets LAP [1] PuSA [1] Aminopeptidase N [1]
IC50 100 nM 150 nM 220 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 μM) treatment leads to the up-regulation of genes involved in amino acid transport and metabolic pathways, the phosphorylation of eukaryotic initiation factor 2α, the inhibition of phosphorylation of mTOR substrates and reduced protein synthesis in HL-60 cells. [1]
In vivo Administration of CHR-2797 (~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]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

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 β-mercaptoethanol. The assay is carried out in 96-well assay plates. Wells contain diluted CHR-2797 (5 μL), 10 μg/mL LAP (5 μL) and 40 μL 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 μL of OPA/β-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 μL), substrate (125 μM Ala-AMC in 0.125 M Tris-HCl buffer, pH 7.5; 40 μL) and enzyme (40 μL). After incubation for 2 hours at 37 °C, the reaction is stopped by addition of 100 μL 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 μL), substrate (40 μL; final concentration, 60 μM) and enzyme (40 μL, 1:8000 dilution) and is incubated for 60 minutes at 37 °C prior to addition of 100 μL 3% (v/v) acetic acid, to stop the reaction. Fluorescence is measured using a SLT Fluostar fluorimeter.

Cell Assay: [1]

Cell lines U-937, HL-60, KG-1, HNT-34 and GDM-1
Concentrations Dissolved in DMSO, final concentration ~1 mM
Incubation Time 72 hours
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 μCi/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.

Animal Study: [1]

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
Formulation Dissolved in DMSO and diluted in saline
Dosages ~100 mg/kg
Administration Dosed daily p.o.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Krige D, et al. Cancer Res, 2008, 68(16), 6669-6679.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-09-01)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01636609 Active, not recruiting Leukemia M.D. Anderson Cancer Center|CTI BioPharma November 2012 Phase 1|Phase 2
NCT01638442 Active, not recruiting Healthy CTI BioPharma|Chroma Therapeutics June 2012 Phase 1
NCT01567059 Completed Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome|Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities|A  ...more Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome|Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities|Adult Acute Myeloid Leukemia With Del(5q)|Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)|de Novo Myelodysplastic Syndromes|Previously Treated Myelodysplastic Syndromes|Secondary Acute Myeloid Leukemia|Secondary Myelodysplastic Syndromes|Untreated Adult Acute Myeloid Leukemia Fred Hutchinson Cancer Research Center|National Cancer Institute (NCI) May 2012 Phase 2
NCT01180426 Active, not recruiting Acute Myeloid Leukemia Chroma Therapeutics June 2010 Phase 2
NCT00780598 Completed Acute Myeloid Leukemia|AML Chroma Therapeutics|Quintiles October 2009 Phase 2

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Chemical Information

Download Tosedostat (CHR2797) SDF
Molecular Weight (MW) 406.47
Formula

C21H30N2O6

CAS No. 238750-77-1
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 51 mg/mL (125 mM)
Water <1 mg/mL (<1 mM)
Ethanol 5 mg/mL (12 mM)
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (S)-cyclopentyl 2-((R)-2-((S)-1-hydroxy-2-(hydroxyamino)-2-oxoethyl)-4-methylpentanamido)-2-phenylacetate

Research Area

Product Citations (2)

Tech Support & FAQs

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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