Tosedostat (CHR-2797)

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Mechanism of action

From the NCI Drug Dictionary: 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. Noxa is a member of the BH3 (Bcl-2 homology 3)-only subgroup of the proapoptotic Bcl-2 (B-cell CLL/lymphoma 2) protein family.

Preliminary Results

Acute myeloid leukemia

  1. OPAL: Cortes J, Feldman E, Yee K, Rizzieri D, Advani AS, Charman A, Spruyt R, Toal M, Kantarjian H. Two dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukaemia (OPAL): a randomised open-label phase 2 study. Lancet Oncol. 2013 Apr;14(4):354-62. Epub 2013 Feb 28. link to original article link to PMC article PubMed
  2. Mawad R, Becker PS, Hendrie P, Scott B, Wood BL, Dean C, Sandhu V, Deeg HJ, Walter R, Wang L, Myint H, Singer JW, Estey E, Pagel JM. Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high-risk MDS. Br J Haematol. 2016 Jan;172(2):238-45. Epub 2015 Nov 16. link to original article PubMed