Tosedostat

Tosedostat (CHR-2797, CHR2797) is a potent, orally bioavailable aminopeptidases inhibitor with IC50 of 150, 220 and 100 nM for PuSA, aminopeptidase N and leucine aminopeptidase, respectively; exerts antiproliferative effects against a range of tumor cell lines in vitro and in vivo and shows selectivity for transformed over nontransformed cells; inhibits phosphorylation of mTOR substrates and reduces protein synthesis in HL-60 cells.Blood Cancer Phase 2 Clinical (In Vitro) :Treatment of HL-60 cells with Tosedostat (CHR-2797) leads to an increase in the secretion of Stanniocalcin 2 (STC2) protein into the growth medium. Increases in SLC7A11 expression are detectable at 60 nM Tosedostat and as early as 2 h posttreatment. The IC50s for inhibition of proliferation by Tosedostat in U-937 and HuT 78 cell lines are 10 nM and >10 μM, respectively. Tosedostat treatment increases expression of amino acid deprivation response (AADR) genes in U-937 cells but not in HuT 78 cells. By 24 h with 0.01 μM Tosedostat the mean MCA production is reduced to 77.8% of the untreated control cells; similarly the MCA production is reduced to 51.3% with 1 μM, 38.5% with 5 μM, and 35.3% with 10 μM Tosedostat. (In Vivo) :Tosedostat (CHR-2797) is active as an anticancer agent in vivo in rodent cancer models, and a dose-response relationship has been shown in two models. The effect of Tosedostat is less apparent when the tumor burden is higher before treatment.