Tosedostat (CHR2797)

Tosedostat (CHR-2797) is an orally active aminopeptidase inhibitor. CHR-2797 exerts antiproliferative effects against a range of tumor cell lines.

Product information

CAS Number: 238750-77-1

Molecular Weight: 406.47

Formula: C21H30N2O6

Synonym:

CHR2797

CHR-2797

CHR 2797

Chemical Name: cyclopentyl (2S)-2-[(2R, 3S)-3-hydroxy-3-(hydroxycarbamoyl)-2-(2-methylpropyl)propanamido]-2-phenylacetate

Smiles: CC(C)C[C@H]([C@H](O)C(=O)NO)C(=O)N[C@@H](C1=CC=CC=C1)C(=O)OC1CCCC1

InChiKey: FWFGIHPGRQZWIW-SQNIBIBYSA-N

InChi: InChI=1S/C21H30N2O6/c1-13(2)12-16(18(24)20(26)23-28)19(25)22-17(14-8-4-3-5-9-14)21(27)29-15-10-6-7-11-15/h3-5,8-9,13,15-18,24,28H,6-7,10-12H2,1-2H3,(H,22,25)(H,23,26)/t16-,17+,18+/m1/s1

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Solubility (25°C) DMSO: 51 mg/mL(125.47 mM). Water: Insoluble.

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

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.

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.

References:

1. Krige D, et al. CHR-2797: an antiproliferative aminopeptidase inhibitor that leads to amino acid deprivation in human leukemic cells. Cancer Res. 2008 Aug 15;68(16):6669-79.
2. Jenkins C, et al. Aminopeptidase inhibition by the novel agent CHR-2797 (tosedostat) for the therapy of acute myeloid leukemia. Leuk Res. 2011 May;35(5):677-81.
3. Smith EM, et al. The combination of HDAC and aminopeptidase inhibitors is highly synergistic in myeloma and leads to disruption of the NFκB signalling pathway. Oncotarget. 2015 Jul 10;6(19):17314-27.

Products are for research use only. Not for human use.