Tosedostat (CHR2797)

Catalog No.S1522

For research use only.

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.

Tosedostat (CHR2797) Chemical Structure

CAS No. 238750-77-1

Selleck's Tosedostat (CHR2797) has been cited by 3 Publications

Purity & Quality Control

Choose Selective Aminopeptidase Inhibitors

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]
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]

Protocol (from 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 Research:[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.
  • (Only for Reference)
Animal Research:[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
  • Dosages: ~100 mg/kg
  • Administration: Dosed daily p.o.
  • (Only for Reference)

Solubility (25°C)

In vitro

DMSO 51 mg/mL
(125.47 mM)
Ethanol 5 mg/mL
(12.3 mM)
Water 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 Information

Molecular Weight 406.47
Formula

C21H30N2O6

CAS No. 238750-77-1
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CC(C)CC(C(C(=O)NO)O)C(=O)NC(C1=CC=CC=C1)C(=O)OC2CCCC2

In vivo Formulation Calculator (Clear solution)

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Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
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Molarity Calculator

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Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT01180426 Unknown status Drug: CHR-2797 Acute Myeloid Leukemia Chroma Therapeutics June 2010 Phase 2
NCT00780598 Completed Drug: Tosedostat Acute Myeloid Leukemia|AML Chroma Therapeutics|Quintiles Inc. October 2009 Phase 2
NCT00522938 Terminated Drug: CHR-2797 (tosedostat)|Drug: erlotinib Carcinoma Non-Small-Cell Lung Chroma Therapeutics December 2007 Phase 1|Phase 2
NCT00737555 Completed Drug: CHR-2797 Solid Tumor Chroma Therapeutics August 2006 Phase 1
NCT00689000 Completed Drug: CHR-2797 (tosedostat): Aminopeptidase inhibitor Acute Myeloid Leukemia|Myelodysplastic Syndrome|Multiple Myeloma Chroma Therapeutics May 2006 Phase 1|Phase 2

(data from https://clinicaltrials.gov, updated on 2022-01-17)

Tech Support

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.

Handling Instructions

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