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Products are for research use only. Not for human use. We do not sell to patients.
(ARQ197; ARQ-197; ARQ 197)
Tivantinib Chemical Structure
|Product name: Tivantinib|
|Cat. No.: HY-50686|
Tivantinib (ARQ 197) is the first non-ATP-competitive c-Met inhibitor with Ki of 0.355 μM, little activity to Ron, and no inhibition to EGFR, InsR, PDGFRα or FGFR1/4.
IC50 value: 0.355 μM(Ki)
in vitro: ARQ-197 has been shown to prevent HGF/c-met induced cellular responses in vitro. ARQ-197 possesses antitumor activity; inhibiting proliferation of A549, DBTRG and NCI-H441 cells with IC50 of 0.38, 0.45, 0.29 μM. Treatment with ARQ-197 results in a decrease in phosphorylation of the MAPK signaling cascade and prevention of invasion and migration. In addition, ectopic expression of c-Met in NCI-H661, a cell line having no endogenous expression of c-Met, causes it to acquire an invasive phenotype that is also suppressed by ARQ-197. Although the addition of increasing concentrations of ARQ-197 does not significantly affect the Km of ATP, exposure of c-Met to 0.5 μM ARQ-197 decreased the Vmax of c-Met by approximately 3-fold. The ability of ARQ-197 to decrease the Vmax without affecting the Km of ATP confirmed that ARQ-197 inhibits c-Met through a non–ATP-competitive mechanism and may therefore account for its high degree of kinase selectivity. ARQ-197 prevents human recombinant c-Met with a calculated inhibitory constant Ki of approximately 355 nM. Although the highest concentration of ATP used is 200 μM, the potency of ARQ-197 against c-Met is not reduced by using concentrations of ATP up to 1 mM. ARQ-197 blocks c-Met phosphorylation and downstream c-Met signaling pathways. ARQ-197 suppresses constitutive and ligand-mediated c-Met autophosphorylation and, by extension, c-Met activity, in turn leading to the inhibition of downstream c-Met effectors. ARQ-197 induction of caspase-dependent apoptosis is increased in c-Met–expressing human cancer cells including HT29, MKN-45, and MDA-MB-231 cells .
in vivo: All three xenograft models treated with ARQ-197 display reductions in tumor growth: 66% in the HT29 model, 45% in the MKN-45 model, and 79% in the MDA-MB-231 model. In these xenograft studies, no significant body weight changes following oral administration of ARQ-197 at 200 mg/kg are observed. Pharmacodynamically, the phosphorylation of c-Met in human colon xenograft tumors (HT29) is strongly inhibited by ARQ-197, as assessed by a dramatic reduction of c-Met autophosphorylation 24 hours after a single oral dose of 200 mg/kg of ARQ-197. This same dosage in mice exhibits that tumor xenografts are exposed to sustained plasma levels of ARQ-197, consistent with the observed pharmacodynamic inhibition of c-Met phosphorylation and inhibition of proliferation of c-Met harboring cancer cell lines. Plasma levels of ARQ-197 10 hours after dosing are determined to be 1.3 μM, more than 3-fold above the biochemical inhibitory constant of ARQ-197 for c-Met. Therefore, ARQ-197 is able to suppress its target in vivo in the xenografted human tumor tissue. In conclusion, ARQ-197 inhibits the growth of c-Met-dependent xenografted human tumors .
|M.Wt||369.42||Storage||Please store the product under the recommended conditions in the Certificate of Analysis.|
|Solvent & Solubility||
200 mM in DMSO
|1 mg||5 mg||10 mg|
|1 mM||2.7069 mL||13.5347 mL||27.0695 mL|
|5 mM||0.5414 mL||2.7069 mL||5.4139 mL|
|10 mM||0.2707 mL||1.3535 mL||2.7069 mL|
|Product Name||Sponsor Only||Condition||Start Date||End Date||Phase||Last Change Date|
|Tivantinib||Daiichi Sankyo Co Ltd||Metastatic non small cell lung cancer||30-NOV-10||31-JUL-13||Phase 3||07-OCT-13|
|Daiichi Sankyo Inc||Hepatocellular carcinoma||31-DEC-12||31-DEC-15||Phase 3||16-OCT-13|
|Istituto Clinico Humanitas||Metastatic colorectal cancer||31-MAR-13||30-JUN-15||Phase 2||08-JUL-13|
|Kyowa Hakko Kirin Co Ltd||Metastatic non small cell lung cancer||31-JUL-11||Phase 3||26-MAR-13|
|National Cancer Institute||Mesothelioma||31-JAN-13||28-FEB-15||Phase 2||23-OCT-13|
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AMG-208 is a potent small molecular c-Met inhibitor with an IC50 of 9.3 nM.
AMG-337 is a potent and highly selective small molecule ATP-competitive MET kinase inhibitor. AMG 337 inhibits MET kinase activity with an IC50 of < 5nM in enzymatic assays.
BMS-777607 is a Met-related inhibitor for c-Met, Axl, Ron and Tyro3 with IC50 of 3.9 nM, 1.1 nM, 1.8 nM and 4.3 nM, 40-fold more selective for Met-related targets versus Lck, VEGFR-2, and TrkA/B, and more than 500-fold greater selectivity versus all other receptor and non receptor kinases.
BMS-794833 is a potent ATP competitive inhibitor of Met/VEGFR2 with IC50 of 1.7/15 nM; also inhibits Ron, Axl and Flt3 with IC50 of <3 nM; a prodrug of BMS-817378.
c-Met inhibitor 1 is an inhibitor of the c-Met receptor signaling pathway useful for the treatment of cancer including gastric, glioblastoma, and pancreatic cancer.
c-Met inhibitor 2 is a potent compound that has activity against cancers dependent upon Met activation and also has activity against cancers as a VEGFR inhibitor.
E7050(Golvatinib) is a dual c-Met and VEGFR-2 inhibitor with IC50 of 14 nM and 16 nM.
EMD 1214063 is a potent and selective c-Met inhibitor with IC50 of 4 nM, >200-fold selective for c-Met than IRAK4, TrkA, Axl, IRAK1, and Mer.
Foretinib (GSK1363089; XL880; EXEL-2880; GSK089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met and KDR with IC50 of 0.4 nM and 0.9 nM. Less potent against Ron, Flt-1/3/4, Kit, PDGFR(alpha)/(beta) and Tie-2, and little activity to FGFR1 and EGFR.