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CHR-2797: An Antiproliferative Aminopeptidase Inhibitor that Leads to Amino Acid Deprivation in Human Leukemic Cells

2008; American Association for Cancer Research; Volume: 68; Issue: 16 Linguagem: Inglês

10.1158/0008-5472.can-07-6627

1538-7445

David Krige, Lindsey Needham, Lindsay J. Bawden, Nicolás Flores, Hannah Farmer, Lauren E.C. Miles, Erica L. Stone, Juliana Callaghan, Stephen Chandler, Vanessa Clark, Patricia Kirwin-Jones, Valérie Legris, Jo Owen, Thakor Patel, Steve Wood, Gary Box, David Laber, Rajesh Odedra, Annette Wright, L. Michael Wood, Suzanne A. Eccles, Elisabeth A. Bone, Andrew Ayscough, Alan H. Drummond,

Ubiquitin and proteasome pathways

Abstract CHR-2797 is a novel metalloenzyme inhibitor that is converted into a pharmacologically active acid product (CHR-79888) inside cells. CHR-79888 is a potent inhibitor of a number of intracellular aminopeptidases, including leucine aminopeptidase. CHR-2797 exerts antiproliferative effects against a range of tumor cell lines in vitro and in vivo and shows selectivity for transformed over nontransformed cells. Its antiproliferative effects are at least 300 times more potent than the prototypical aminopeptidase inhibitor, bestatin. However, the mechanism by which inhibition of these enzymes leads to proliferative changes is not understood. Gene expression microarrays were used to profile changes in mRNA expression levels in the human promyelocytic leukemia cell line HL-60 treated with CHR-2797. This analysis showed that CHR-2797 treatment induced a transcriptional response indicative of amino acid depletion, the amino acid deprivation response, which involves up-regulation of amino acid synthetic genes, transporters, and tRNA synthetases. These changes were confirmed in other leukemic cell lines sensitive to the antiproliferative effects of CHR-2797. Furthermore, CHR-2797 treatment inhibited phosphorylation of mTOR substrates and reduced protein synthesis in HL-60 cells, both also indicative of amino acid depletion. Treatment with CHR-2797 led to an increase in the concentration of intracellular small peptides, the substrates of aminopeptidases. It is suggested that aminopeptidase inhibitors, such as CHR-2797 and bestatin, deplete sensitive tumor cells of amino acids by blocking protein recycling, and this generates an antiproliferative effect. CHR-2797 is orally bioavailable and currently undergoing phase II clinical investigation in the treatment of myeloid leukemia. [Cancer Res 2008;68(16):6669–79]