For research use only.
CAS No. 238750-77-1
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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Choose Selective Aminopeptidase Inhibitors
|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.|
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. 
|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. |
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.
|In vitro||DMSO||51 mg/mL (125.47 mM)|
|Ethanol||5 mg/mL (12.3 mM)|
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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|
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