title: CHR-2797: an antiproliferative aminopeptidase inhibitor that leads to amino acid deprivation in human leukemic cells.
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.
authors.affiliation: Chroma Therapeutics Ltd., Abingdon, United Kingdom. dkrige@chromatherapeutics.com
authors.forename: David
authors.initials: D
authors.lastname: Krige
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Needham
authors.forename: Lindsay J
authors.initials: LJ
authors.lastname: Bawden
authors.forename: Nicolas
authors.initials: N
authors.lastname: Flores
authors.forename: Hannah
authors.initials: H
authors.lastname: Farmer
authors.forename: Lauren E C
authors.initials: LE
authors.lastname: Miles
authors.forename: Erica
authors.initials: E
authors.lastname: Stone
authors.forename: Juliana
authors.initials: J
authors.lastname: Callaghan
authors.forename: Stephen
authors.initials: S
authors.lastname: Chandler
authors.forename: Vanessa L
authors.initials: VL
authors.lastname: Clark
authors.forename: Patricia
authors.initials: P
authors.lastname: Kirwin-Jones
authors.forename: Valérie
authors.initials: V
authors.lastname: Legris
authors.forename: Jo
authors.initials: J
authors.lastname: Owen
authors.forename: Thakor
authors.initials: T
authors.lastname: Patel
authors.forename: Steve
authors.initials: S
authors.lastname: Wood
authors.forename: Gary
authors.initials: G
authors.lastname: Box
authors.forename: David
authors.initials: D
authors.lastname: Laber
authors.forename: Rajesh
authors.initials: R
authors.lastname: Odedra
authors.forename: Annette
authors.initials: A
authors.lastname: Wright
authors.forename: L Michael
authors.initials: LM
authors.lastname: Wood
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Bone
authors.forename: Andrew
authors.initials: A
authors.lastname: Ayscough
authors.forename: Alan H
authors.initials: AH
authors.lastname: Drummond
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D015151:Immunoblotting; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D011500:Protein Synthesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases; D013876:Thiophenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000596:Amino Acids; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D006877:Hydroxamic Acids; C498702:PMAIP1 protein, human; D010446:Peptide Fragments; D011500:Protein Synthesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D000626:Aminopeptidases; D007930:Leucine; C012211:ubenimex; C531970:tosedostat; D005998:Glycine