Target Validation Information
Target ID T15610
Target Name Puromycin-sensitive aminopeptidase
Target Type
Clinical Trial
Drug Potency against Target CHR-2797 Drug Info IC50 = 150 nM [552966]
Action against Disease Model CHR-2797 CHR-79888 is a potent inhibitor of a n uMber of intracellular aminopeptidases, including leucine aminopeptidase. CHR-2797 treatment in the h uMan promyelocytic leukemia cell line HL-60 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. [536813] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations A major function of proteasomes and macroautophagy is to eliminate misfolded potentially toxic proteins. Mammalian proteasomes, however, cannot cleave polyglutamine (polyQ) sequences and seem to release polyQ-rich peptides. Puromycin-sensitive aminopeptidase (PSA) is the only cytosolic enzyme able to digest polyQ sequences. We tested whether PSA can protect against acc uMulation of polyQ fragments. In cultured cells, Drosophila and mouse muscles, PSA inhibition or knockdown increased aggregate content and toxicity of polyQ-expanded huntingtin exon 1. Conversely, PSA overexpression decreased aggregate content and toxicity. PSA inhibition also increased the levels of polyQ-expanded ataxin-3 as well as mutant |?-synuclein and superoxide dismutase 1. These protective effects result from an unexpected ability of PSA to enhance macroautophagy. PSA overexpression increased, and PSA knockdown or inhibition reduced microtubule-associated protein 1 light chain 3-II (LC3-II) levels and the amount of protein degradation sensitive to inhibitors of lysosomal function and autophagy. Thus, by promoting autophagic protein clearance, PSA helps protect against acc uMulation of aggregation-prone proteins and proteotoxicity. [552966]
References
Ref 552966A first-in-man phase i and pharmacokinetic study on CHR-2797 (Tosedostat), an inhibitor of M1 aminopeptidases, in patients with advanced solid tumors. Clin Cancer Res. 2009 Aug 1;15(15):4978-85. doi: 10.1158/1078-0432.CCR-09-0306. Epub 2009 Jul 28.
Ref 536813CHR-2797: an antiproliferative aminopeptidase inhibitor that leads to amino acid deprivation in human leukemic cells. Cancer Res. 2008 Aug 15;68(16):6669-79.

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