Systematic name M8144
Brief description Genes up-regulated in HL-60 cells (acute promyelocytic leukemia, APL) after treatment with the aminopeptidase inhibitor tosedostat (CHR-2797) [PubChem=15547703] for 6 h.
Full description or 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.
Collection C2: curated gene sets
      CGP: chemical and genetic perturbations
Source publication Pubmed 18701491   Authors: Krige D,Needham LA,Bawden LJ,Flores N,Farmer H,Miles LE,Stone E,Callaghan J,Chandler S,Clark VL,Kirwin-Jones P,Legris V,Owen J,Patel T,Wood S,Box G,Laber D,Odedra R,Wright A,Wood LM,Eccles SA,Bone EA,Ayscough A,Drummond AH
Exact source Table 4S: 6hr
Related gene sets (show 4 additional gene sets from the source publication)
External links  
Organism Homo sapiens
Contributed by Jessica Robertson (Broad Institute)
Source platform HG-U133_Plus_2
Dataset references  
Download gene set format: grp | text | gmt | gmx | xml
Compute overlaps (show collections to investigate for overlap with this gene set)
Compendia expression profiles Human tissue compendium (Novartis)
NCI-60 cell lines (National Cancer Institute)
Advanced query Further investigate these 953 genes
Gene families Categorize these 953 genes by gene family
Show members (show 1244 members mapped to 953 genes)
Version history 3.0: First introduced

See MSigDB license terms here. Please note that certain gene sets have special access terms.