MK-8033 hydrochloride

MK-8033 hydrochloride is an orally active ATP competitive c-Met/Ron dual inhibitor ( IC 50 s: 1 nM (c-Met),7 nM (Ron)), with preferential binding to the activated kinase conformation. MK-8033 hydrochloride can be used in the research of cancers, such as breast and bladder cancers, non-small cell lung cancers (NSCLCs) In Vitro MK-8033 hydrochloride (Compound 11r, 10 μM) displayed 31% inhibition of CYP3A4 (cytochrome P450 3A4). MK-8033 hydrochloride (1 μM, 2 h) inhibits phosphorylation of Y1349 of c-Met (IC 50 : 0.03 μM) in the c-Met dependent gastric cancer cell line GTL-16. MK-8033 hydrochloride (1-10 μM, 72 h) inhibits GTL-16 cell proliferation (IC 50 : 0.58 μM). MK-8033 hydrochloride binds more tightly to phosphorylated c-Met (K d : 3.2 nM) than to its unphosphorylated counterpart (K d : 10.4 nM), and inhibits oncogenic c-Met activation loop mutants with IC 50 s ranging from 0.6 to 1 nM. MK-8033 hydrochloride (0.1-10 μM, 2 h) reduces the phosphorylation of c-Met, ERK, and Akt in EBC-1 and H1993 cells. MK-8033 hydrochloride (1 μM, 1 h) sensitizes EBC-1 and H1993 cells (high c-Met-expressing) to radiation. MK-8033 hydrochloride (10 μM, 6 h) enhances γ-H2Ax levels in A549 cells compared to double irradiation and decreases in DNA repair. MK-8033 hydrochloride (2 μM, 72 h) results in reduced cell proliferation, but modest induction of apoptosis in G-alpha protein mutant UM (uveal melanoma) cells. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Western Blot AnalysisCell Line: EBC-1, H1993 cells, A549 and H460 cells Concentration: 0.1, 1, 10 μM Incubation Time: 2 h Result: Reduced the phosphorylation of c-Met, ERK, and Akt in EBC-1 and H1993 cells in a dose-dependent manner. In Vivo MK-8033 hydrochloride (Compound 11r, oral administration, 3-100 mg/kg, twice daily for 21 days) inhibits tumor growth in GTL-16 c-Met amplified gastric tumor xenografts . MK-8033 hydrochloride exhibits moderate clearance (t 1/2 : 0.8 h for rats, 3.1 h for dog) and favorable bioavailability (35% for rats, 33% for dog) . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Human GTL-16 c-Met amplified gastric tumor xenografts Dosage: 3, 10, 30, and 100 mg/kg Administration: Oral administration, twice daily for 21 days Result: Resulted in 22, 18, 57, and 86% tumor growth inhibition at 3, 10, 30, and 100 mg/kg, respectively. Inhibited c-Met (Y1349) phosphorylation. Form:Solid IC50& Target:IC50: 7 nM (Ron)

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