ARQ 197 binds to an inactive, or nonphosphorylated, conformation of MET and locks it in this inactive state. Kinetic analyses of ARQ 197 demonstrate substantial in vitro potency as well as a non ATP aggressive mechanism of action, which can Hedgehog Pathway explain a substantial degree of kinase selectivity that distinguishes the compound from other MET inhibitors. ARQ 197 inhibits each constitutive and ligandmediated MET autophosphorylation in diverse human cancer cell lines, with a 50% inhibitory concentration of a hundred 300 nM, in turn inhibiting downstream MET effectors Akt, Erk 1/2, and STAT three. Maximal MET inhibition is achieved by 24 hours, and it may be sustained for as much as eight 12 hours following withdrawal of ARQ 197, demonstrating prolonged durability of MET kinase receptor inhibition. ARQ 197 also inhibits HGF induced phosphorylation of MET and HGF induced downstream targets, such as ERK1/2, MEK1/2, and FAK. In Vivo Studies Xenograft mouse designs using several human cancer cell lines demonstrate marked antitumor activity with orally administered ARQ 197 200 mg/kg, as indicated by sizeable tumor development reductions ranging from 45% to 79% in colon, gastric, breast, prostate, and pancreatic cancer models.
Compared with control animals, the degree of phospho MET was drastically reduced in immunosuppressed mice with established HT 29 human colon cancer 24 hrs Olaparib price immediately after administration of a single oral dose of ARQ 197 .
Moreover, tumor xenografts had been exposed to sustainedARQ197 plasma levels following a single oral dose of 200 mg/kg in mice, consistent with concentrations shown to inhibit MET enzymatic activity and proliferation of MET harboring cancer cell lines in vitro. ARQ 197 plasma ranges 10 hours just after dosing have been 1.three M increased than threefold above the ARQ 197 Ki for MET. ARQ 197 also demonstrated the capacity to avoid bone metastases within a humanized mouse model of metastatic breast cancer, as well as considerable inhibition of liver metastases in murine xenograft models of human cancer. Preclinical Pharmacokinetics and Metabolism Studies of individual human cytochrome P450 isozymes demonstrate that ARQ 197 is quickly metabolized by CYP2C19 and moderately metabolized by CYP3A4 . ARQ 197 won’t appear to become a powerful inhibitor of any with the big CYP450 enzymes tested. Metabolic research in rat, canine, mouse, and human hepatocytes indicate that oxidative biotransformation could be the key metabolic pathway. Around the basis of pharmacokinetic information, oral bioavailability was 20% from the species investigated: mouse, rat, and canine. CLINICAL Improvement Pharmacokinetic Information Evaluation of ARQ 197 PK parameters was carried out for studies ARQ 197 101, ARQ 197 103, ARQ 197 111, ARQ 197 114, ARQ 197 204, ARQ 197 116, and ARQ 197 117 .