TOSEDOSTAT: INHIBITING AMINOPEPTIDASES IN CANCERS

by Selleckchem | Mar 18 2012

AMINOPEPTIDASES AND THEIR INHIBITION:

Aminopeptidases catalyze the cleavage of amino acids of proteins or peptide substrates. Such enzymes are zinc dependant and located throughout most mammalian tissue and in certain plant extracts. They are essential for many cellular maintenance functions and are release systemically from the small intestine. Since these enzymes act by hydrolysis amino acids located at the amino groups of terminal proteins inhibition of their processes would affect cell proliferation, secretion, invasion and angiogenesis. Small molecule inhibitors for the inhibition of aminopeptidases have been developed for oncological use. CHR-2797 is a pro-drug for an aminopeptidase inhibitor that is marketed by Chroma Therapeutics under the trade name of Tosedostat. Tosedostat aminopeptidase inhibitor under goes cellular modulation to the active metabolite (CHR79888) via hydrolysis of a methoxy group. This metabolite is poorly membrane permeable, resulting in cellular accumulation. In animal models Toseostad has proved to be a significant inhibitor of proliferation and has demonstrated anti-angiogenic activity.[1;2]

Tosedostat: Properties and Availability

Tosedostat structure is described as α-[[(2R)-2-[(1S)-1-Hydroxy-2-(hydroxyamino)-2-oxoethyl]-4-methyl-1-oxopentyl]amino]-benzeneacetic acid cyclopently ester and is available in high purity from a variety of Tosedostat suppliers. Tosedostat price varies between suppliers ranging from $90 – 150 for a 10 mg vial, to buy Tosedostat researchers are advised to shop carefully to obtain the best value for money. For Tosedostat stability in solution it is recommended that all stocks be stored at -20°C and freeze/thaw cycles be kept to a minimum. For stability of the solid form it is also recommended to store under nitrogen or desiccated conditions at 4°C or lower and protect from light. Tosedostat solubility in DMSO is up to 100 mM but will also dissolve in ethanol to 50 nM.

Tosedostat: Preclinical and Clinical status

Tosedostat has been reported as being a prodrug metabolised inside cell to an active acid product (CHR-79888) [2]. Tosedostat IC50 for a number of intracellular aminopeptidases has been reported to range from 100-220 nM, while for others its ranges from 1000 – 10000 nM. The more sensitive aminopeptidases Leucyl aminopeptidases (100 nM), puromycin-sensitive aminopeptidase (150 nM) and aminopeptidase N (220 nM) respectively. A investigation into the mechanism of action for Tosedostad used HL-60 (human promyelocytic leukemia) cell line to monitor genetic profiles for placebo and treated conditions. The conclusion from this investigation indicated that Tosedostad induced up regulation of amino acid synthetic genes, transporters and tRMA synthetases, it also induced phosphorylation of mTOR. These were a typical responses if an amino acid depletion is induced in a cell. The general suggest, therefore was that Tosedostad blocked protein recycling hence depleted sensitive tumor cells of essential amino acids. The end result being proliferation being inhibited. [3-5] These results were sufficient to move to phase 1 Tosedostat clinical trials. The first reported trial was in patients with advanced solid tumors, this phase one trial determined that CHR-2797 was well tolerated in doses that achieve concentrations in the cell of CHR79888 that are associated with activity.[1] The result of this trial was to recommend single agent therapy at a dose of 240 mg/day for this molecule. A similar trial in combination with paclitaxel reported over 50% response rate with most being stable disease.[6] A second dose tolerance study was conducted in hematological malignancies and in elderly / relapsing acute myeloid leukemia. The results of these investigations was that a daily dose of 130 mg was significantly active and with a minimum of toxicity.[7]. Tosedostad is currently in further phase 2 and phase 3 testing with results expected in 2013.

References

1. Reid AH, Protheroe A et al. A first-in-man phase i and pharmacokinetic study on CHR-2797 (Tosedostat), an inhibitor of M1 aminopeptidases, in patients with advanced solid tumors. Clin Cancer Res 2009; 15(15):4978-4985.

2. Krige D, Needham LA et al. CHR-2797: an antiproliferative aminopeptidase inhibitor that leads to amino acid deprivation in human leukemic cells. Cancer Res 2008; 68(16):6669-6679.

3. Wickstrom M, Larsson R et al. Aminopeptidase N (CD13) as a target for cancer chemotherapy. Cancer Sci 2011; 102(3):501-508.

4. Jenkins C, Hewamana S et al. Aminopeptidase inhibition by the novel agent CHR-2797 (tosedostat) for the therapy of acute myeloid leukemia. Leuk Res 2011; 35(5):677-681.

5. Moore HE, Davenport EL et al. Aminopeptidase inhibition as a targeted treatment strategy in myeloma. Mol Cancer Ther 2009; 8(4):762-770.

6. van Herpen CM, Eskens FA et al. 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. Br J Cancer 2010; 103(9):1362-1368.

7. Lowenberg B, Morgan G et al. Phase I/II clinical study of Tosedostat, an inhibitor of aminopeptidases, in patients with acute myeloid leukemia and myelodysplasia. J Clin Oncol 2010; 28(28):4333-4338.