Tosedostat
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MedKoo CAT#: 205648

CAS#: 238750-77-1

Description: Tosedostat is a proprietary orally bioavailable inhibitor of the M1 family of aminopeptidases with potential antineoplastic activity. Tosedostat is converted intracellularly into a poorly membrane-permeable active metabolite (CHR-79888) which inhibits the M1 family of aminopeptidases, particularly puromycin-sensitive aminopeptidase (PuSA), and leukotriene A4 (LTA4) hydrolase; inhibition of these aminopeptidases in tumor cells may result in amino acid deprivation, inhibition of protein synthesis due to a decrease in the intracellular free amino acid pool, an increase in the level of the proapoptotic protein Noxa, and cell death.


Chemical Structure

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Tosedostat
CAS# 238750-77-1

Theoretical Analysis

MedKoo Cat#: 205648
Name: Tosedostat
CAS#: 238750-77-1
Chemical Formula: C21H30N2O6
Exact Mass: 406.21
Molecular Weight: 406.470
Elemental Analysis: C, 62.05; H, 7.44; N, 6.89; O, 23.62

Price and Availability

Size Price Availability Quantity
5mg USD 150 Ready to ship
10mg USD 250 Ready to ship
25mg USD 550 Ready to ship
50mg USD 950 Ready to ship
100mg USD 1650 Ready to Ship
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Synonym: CHR2797; CHR-2797; CHR 2797; Tosedostat.

IUPAC/Chemical Name: (S)-cyclopentyl 2-((R)-2-((S)-1-hydroxy-2-(hydroxyamino)-2-oxoethyl)-4-methylpentanamido)-2-phenylacetate

InChi Key: FWFGIHPGRQZWIW-SQNIBIBYSA-N

InChi Code: 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

SMILES Code: O=C(OC1CCCC1)[C@@H](NC([C@@H]([C@H](O)C(NO)=O)CC(C)C)=O)C2=CC=CC=C2

Appearance: Solid powder

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

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:        

Biological target: Tosedostat (CHR-2797) is an orally active aminopeptidase inhibitor. CHR-2797 exerts antiproliferative effects against a range of tumor cell lines.
In vitro activity: The mechanistic link between aminopeptidase inhibition and antiproliferative effects was investigated by gene expression profiling in HL-60 cells treated with CHR-2797. Cells were treated with vehicle or 6 μmol/L CHR-2797, equivalent to 200× the IC50 for its inhibition of proliferation (30 nmol/L; Fig. 1A). Approximately, 40% of the genes represented on the microarray were expressed in HL-60 cells, and the expression of 2461 of these were increased or decreased by ≥2-fold after treatment with CHR-2797. CHR-2797 treatment also led to the up-regulation of a number of genes which have not previously been described as AADR genes. Treatment of HL-60 cells with CHR-2797 led to an increase in the secretion of STC2 protein into the growth medium (Supplementary Fig. S5).To determine whether the transcriptional effects of CHR-2797 were mediated by this signaling pathway, the levels of phosphorylated (Ser51) eIF2α were measured in HL-60 cells treated with the compound. Amino acid deprivation and treatment with CHR-2797 or bestatin caused an increase in phosphorylated eIF2α ( Fig. 3A) In HL-60 cells, amino acid deprivation and treatment with bestatin or CHR-2797, but not its inactive analogue, CHR-3204, caused a decrease in the phosphorylation of both S6 kinase (Thr389) and 4E-BP1 (Thr37/46) at sites controlled by mTOR signaling ( Fig. 3B and C) As CHR-2797 treatment inhibited the phosphorylation of key mTOR substrates, the effects of the compound on protein synthesis were measured. As expected, CHR-2797 treatment inhibited protein synthesis in HL-60 cells at concentrations as low as 0.06 μmol/L ( Fig. 3D). These effects were much less pronounced in HuT 78 cells. The potential for synergy between CHR-2797 and agents targeting amino acid transporters is an obvious avenue to be explored. Reference: Res. 2008 Aug 15;68(16):6669-79. https://cancerres.aacrjournals.org/content/68/16/6669.long
In vivo activity: The efficacy of CHR-2797 has been investigated in a range of in vivo tumor models, including syngeneic rat and human tumor xenografts. CHR-2797 is active as an anticancer agent in vivo in rodent cancer models, and a dose-response relationship has been shown in two models. The effect of CHR-2797 is less apparent when the tumor burden is higher before treatment (Supplementary Fig. S4). Reference: Res. 2008 Aug 15;68(16):6669-79. https://cancerres.aacrjournals.org/content/68/16/6669.long

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 42.0 103.33
Ethanol 28.0 68.89

Preparing Stock Solutions

The following data is based on the product molecular weight 406.47 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Krige D, Needham LA, Bawden LJ, Flores N, Farmer H, Miles LE, Stone E, Callaghan J, Chandler S, Clark VL, Kirwin-Jones P, Legris V, Owen J, Patel T, Wood S, Box G, Laber D, Odedra R, Wright A, Wood LM, Eccles SA, Bone EA, Ayscough A, Drummond AH. 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. doi: 10.1158/0008-5472.CAN-07-6627. PMID: 18701491. 2. Anbalagan S, Biasoli D, Leszczynska KB, Mukherjee S, Hammond EM. In Vitro Radiosensitization of Esophageal Cancer Cells with the Aminopeptidase Inhibitor CHR-2797. Radiat Res. 2015 Sep;184(3):259-65. doi: 10.1667/RR14150.1. Epub 2015 Aug 20. PMID: 26291737.
In vitro protocol: 1. Krige D, Needham LA, Bawden LJ, Flores N, Farmer H, Miles LE, Stone E, Callaghan J, Chandler S, Clark VL, Kirwin-Jones P, Legris V, Owen J, Patel T, Wood S, Box G, Laber D, Odedra R, Wright A, Wood LM, Eccles SA, Bone EA, Ayscough A, Drummond AH. 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. doi: 10.1158/0008-5472.CAN-07-6627. PMID: 18701491. 2. Anbalagan S, Biasoli D, Leszczynska KB, Mukherjee S, Hammond EM. In Vitro Radiosensitization of Esophageal Cancer Cells with the Aminopeptidase Inhibitor CHR-2797. Radiat Res. 2015 Sep;184(3):259-65. doi: 10.1667/RR14150.1. Epub 2015 Aug 20. PMID: 26291737.
In vivo protocol: 1. Krige D, Needham LA, Bawden LJ, Flores N, Farmer H, Miles LE, Stone E, Callaghan J, Chandler S, Clark VL, Kirwin-Jones P, Legris V, Owen J, Patel T, Wood S, Box G, Laber D, Odedra R, Wright A, Wood LM, Eccles SA, Bone EA, Ayscough A, Drummond AH. 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. doi: 10.1158/0008-5472.CAN-07-6627. PMID: 18701491.

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1. Aminopeptidase inhibition by the novel agent CHR-2797 (tosedostat) for the therapy of acute myeloid leukemia By Jenkins, Christopher; Hewamana, Saman; Krige, David; Pepper, Chris; Burnett, Alan From Leukemia Research (2011), 35(5), 677-681.

2. Phase I/II clinical study of tosedostat, an inhibitor of aminopeptidases, in patients with acute myeloid leukemia and myelodysplasia By Loewenberg, Bob; Morgan, Gareth; Ossenkoppele, Gert I.; Burnett, Alan K.; Zachee, Pierre; Duehrsen, Ulrich; Dierickx, Daan; Mueller-Tidow, Carsten; Sonneveld, Pieter; Krug, Utz; et al From Journal of Clinical Oncology (2010), 28(28), 4333-4338.

3. A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours By van Herpen, C. M. L.; Eskens, F. A. L. M.; de Jonge, M.; Desar, I.; Hooftman, L.; Bone, E. A.; Timmer-Bonte, J. N. H.; Verweij, J. From British Journal of Cancer (2010), 103(9), 1362-1368.

4. Quinazoline derivatives and methods of treatment By Tung, Roger From U.S. Pat. Appl. Publ. (2010), US 20100260674 A1 20101014.

5. Surface topographies for non-toxic bioadhesion control By Brennan, Anthony B.; Long, Christopher James; Bagan, Joseph W.; Schumacher, James Frederick; Spiecker, Mark M. From U.S. Pat. Appl. Publ. (2010), US 20100226943 A1 20100909.

6. Starving to succeed By Davenport, Emma L.; Aronson, Lauren I.; Davies, Faith E. From Autophagy (2009), 5(7), 1052-1054.

7. Gene expression biomarkers of aminopeptidase inhibition in tumor-derived cell lines By Krige, David; Drummond, Alan Hastings From PCT Int. Appl. (2009), WO 2009098451 A2 20090813.

8. A First-in-Man Phase I and Pharmacokinetic Study on CHR-2797 (Tosedostat), an Inhibitor of M1 Aminopeptidases, in Patients with Advanced Solid Tumors By Reid, Alison H. M.; Protheroe, Andrew; Attard, Gerhardt; Hayward, Nikki; Vidal, Laura; Spicer, James; Shaw, Heather M.; Bone, Elizabeth A.; Carter, Joanne; Hooftman, Leon; et al From Clinical Cancer Research (2009), 15(15), 4978-4985.

9. Tosedostat: aminopeptidase inhibitor oncolytic By Owen, R. T.; Castaner, R.; Bolos, J. From Drugs of the Future (2009), 34(2), 115-118.

10. Aminopeptidase inhibition as a targeted treatment strategy in myeloma By Moore, Hannah E.; Davenport, Emma L.; Smith, Emma M.; Muralikrishnan, Srikanth; Dunlop, Alan S.; Walker, Brian A.; Krige, David; Drummond, Alan H.; Hooftman, Leon; Morgan, Gareth J.; et al From Molecular Cancer Therapeutics (2009), 8(4), 762-770.

11. Dosing schedules of leukotriene synthesis inhibitors for human therapy By Hermann, David J.; Hartman, Daniel L.; Van Ess, Peter James; Wang, Wenping From PCT Int. Appl. (2008), WO 2009002746 A1 20081231.

12. CHR-2797: An Antiproliferative Aminopeptidase Inhibitor that Leads to Amino Acid Deprivation in Human Leukemic Cells By Krige, David; Needham, Lindsey A.; Bawden, Lindsay J.; Flores, Nicolas; Farmer, Hannah; Miles, Lauren E. C.; Stone, Erica; Callaghan, Juliana; Chandler, Stephen; Clark, Vanessa L.; et al From Cancer Research (2008), 68(16), 6669-6679.

13. Preparation of cytostatic hydroxamic acid derivatives of amino acids By Pearson, Lindsey Ann; Ayscough, Andrew Paul; Huxley, Philip; Drummond, Alan From U.S. (2002), US 6462023 B1 20021008.

14. Antibacterial hydroxamic acid derivatives By Hunter, Michael George; Beckett, Raymond Paul; Clements, Martin John; Whittaker, Mark From PCT Int. Appl. (2000), WO 2000044373 A1 20000803.

15. Hydroxamic acid derivatives as inhibitors of beta-amyloid production By Johnstone, Mandy; Ayscough, Andrew Paul From PCT Int. Appl. (2000), WO 2000009119 A1 20000224.

16. Hydroxamic acid derivatives of amino acids as antiinflammatories By Ayscough, Andrew Paul; Whittaker, Mark From PCT Int. Appl. (1999), WO 9940910 A1 19990819.

17. Aminopeptidase N (CD13) as a target for cancer chemotherapy By Wickstrom Malin; Larsson Rolf; Nygren Peter; Gullbo Joachim From Cancer science (2011), 102(3), 501-8.