CHR-2797: an antiproliferative aminopeptidase inhibitor that leads to amino acid deprivation in human leukemic cells.
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.
Krige
David
D
Chroma Therapeutics Ltd., Abingdon, United Kingdom. dkrige@chromatherapeutics.com
Needham
Lindsey A
LA
Bawden
Lindsay J
LJ
Flores
Nicolas
N
Farmer
Hannah
H
Miles
Lauren E C
LE
Stone
Erica
E
Callaghan
Juliana
J
Chandler
Stephen
S
Clark
Vanessa L
VL
Kirwin-Jones
Patricia
P
Legris
Valérie
V
Owen
Jo
J
Patel
Thakor
T
Wood
Steve
S
Box
Gary
G
Laber
David
D
Odedra
Rajesh
R
Wright
Annette
A
Wood
L Michael
LM
Eccles
Suzanne A
SA
Bone
Elisabeth A
EA
Ayscough
Andrew
A
Drummond
Alan H
AH
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
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