Tivantinib

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

Tivantinib (ARQ-197) 是一种有效、选择性、非 ATP 竞争性 c-Met 抑制剂，Ki 为 355 nM。

Tivantinib (ARQ-197)?is a potent, selective, non-ATP-competitive inhibitor of c-Met with Ki of 355 nM; has no inhibition for EGFR, InsR, PDGFRα, FGFR1 and FGFR4 etc., only modest inhibition (35%) for Ron at 30 uM; inhibits constitutive c-Met phosphorylation in HT29 and MKN-45 cells, and HGF-induced c-Met phosphorylation in MDA-MB-231 and NCI-H441 cells with IC50 of 100-300 nM; shows antiproliferative activity against multiple cancer cell lines (IC50=0.03-30 uM); exerts tumor growth inhibition in multiple mouse xenograft; orally active.Liver Cancer Phase 3 Clinical(In Vitro):Tivantinib (ARQ 197) selectively inhibits c-Met activity in cell-free and cell-based assays. c-Met-expressing cancer cell lines treated with Tivantinib display either a dose-dependent loss of proliferative capacity or caspase-dependent apoptosis that positively correlates with either ligand-dependent c-Met activity or constitutively active c-Met. To examine the biochemical mode of inhibition of Tivantinib, kinetic analyses are done using recombinant human c-Met in a filtermat-based assay. The Km of ATP is 50.5±2.2 μM, which is similar to the Km value of ATP. In these kinetic studies, Tivantinib inhibits human recombinant c-Met with a calculated inhibitory constant (Ki) of ~355 nM. In vitro exposure to Tivantinib inhibits constitutive c-Met phosphorylation in HT29 and MKN-45 cells, and HGF-induced c-Met phosphorylation in MDA-MB-231 and NCI-H441 cells with an IC50 of 100 to 300 nM. Tivantinib is a low-molecular-weight compound, and is the first in class orally available selective inhibitor of c-Met. (In Vivo):Pharmacodynamically, the phosphorylation of c-Met in human colon xenograft tumors (HT29) is strongly inhibited by Tivantinib (ARQ 197), as assessed by a dramatic reduction of c-Met autophosphorylation 24 hours after a single oral dose of 200 mg/kg of Tivantinib. This same dosage in mice shows that tumor xenografts are exposed to sustained plasma levels of Tivantinib, consistent with the observed pharmacodynamic inhibition of c-Met phosphorylation and inhibition of proliferation of c-Met harboring cancer cell lines. A Cmax of 5.73 μg/mL (13 μM), an area under the concentration-time curve of 12.1 μg/mL h, and a t1/2 of 2.4 hours are measured. Plasma levels of Tivantinib 10 hours after dosing are determined to be 1.3 μM, >3-fold above the biochemical inhibitory constant of Tivantinib for c-Met.

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ARQ-197

Angiogenesis

c-Met/HGFR

c-Met

Cancer

Liver Cancer

905854-02-6

369.4159

C23H19N3O2

>98% (HPLC)

10 mM in DMSO

O=C([C@@H](C1=CN2CCCC3=C2C1=CC=C3)[C@@H]4C5=CNC6=C5C=CC=C6)NC4=O

2,5-Pyrrolidinedione, 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-, (3R,4R)-

(-20℃)

With Ice Pack

≥ 2 years