PHA-665752

Research use only, not for human use.

PHA-665752 is a potent, selective, ATP-competitive c-Met inhibitor with Ki/IC50 of 4/9 nM.

PHA-665752 is a potent, selective, ATP-competitive c-Met inhibitor with Ki/IC50 of 4/9 nM, inhibits c-Met RTK autophosphorylation in A549 cells with IC50 of 45 nM; exhibits >50-fold selectivity for c-Met against a panel of kinases with exceptions of Ron and VEGFR2 (IC50=68 and 200 nM); inhibited HGF-stimulated or constitutive phosphorylation of mediators of downstream signal transduction of c-Met, including Gab-1, ERK, Akt, STAT3, PLCγ, and FAK in multiple tumor cell lines; inhibits c-Met phosphorylation and tumor growth in vivo.

PHA-665752 is a potent and ATP-competitive inhibitor of c-Met kinase activity with a Ki of 4 nM and an IC50 of 9 nM.PHA-665752 exhibits >50-fold selectivity for c-Met enzyme compared with the majority of kinases evaluated. PHA-665752 shows potent inhibition of c-Met RTK autophosphorylation in NIH3T3 cells engineered to express high levels of c-Met and hepatocyte growth factor (HGF). PHA-665752 inhibits HGF-stimulated or constitutive phosphorylation of mediators of downstream of c-Met such as Gab-1, ERK, Akt, STAT3, PLC-γ, and FAK in multiple tumor cell lines.PHA-665752 (0-1.25 μM; 18 hours) potently inhibits HGF and c-Met-driven phenotypes such as cell growth (proliferation and survival), cell motility, invasion, and/or morphology of a variety of tumor cells.PHA-665752 (0-1.25 μM; 72 hours) induces apoptosis in both the presence and absence of HGF at concentrations that inhibited tyrosine phosphorylation of c-Met in GTL-16 cells.PHA-665752 (0.0125-0.2 μM; 4 hours) potent inhibits HGF-induced c-Met phosphorylation in A549 cells. Cell Proliferation AssayCell Line:S114 cells, GTL-16 cells, NCI-H441 cells, or BxPC-3 cells Concentration:0 μM, 0.002 μM, 0.01 μM, 0.05 μM, 0.25 μM, 1.25 μM Incubation Time:18 hours Result:Potently inhibited HGF and c-Met-driven cell growth.Apoptosis Analysis Cell Line:GTL-16 cells Concentration:0 μM, 0.002 μM, 0.01 μM, 0.05 μM, 0.25 μM, 1.25 μM Incubation Time:72 hours Result:Induced apoptosis in both the presence and absence of HGF at concentrations that inhibited tyrosine phosphorylation of c-Met in GTL-16 cells. Immunoblot Analysis.Western Blot Analysis Cell Line:A549 cells Concentration:0.0125 μM, 0.025 μM,0.05 μM,0.1 μM,0.2 μM Incubation Time:4 hours Result:Potent inhibited HGF-induced c-Met phosphorylation in A549 cells.

PHA-665752 (7.5-30 mg/kg/day; i.v. ; for 9 days) exhibits statistically significant dose-dependent tumor growth inhibition of 68%, 39%, and 20% of vehicle control at the 30 mg/kg/day, 15 mg/kg/day, and 7.5 mg/kg/day doses, respectively.PHA-665752 shows a potent cytoreductive activity in a gastric carcinoma xenograft model. Animal Model:Female athymic mice (nu/nu, 8–12 weeks) bearing S114 or GTL-16 tumor xenografts Dosage:7.5 mg/kg/day, 15 mg/kg/day, 30 mg/kg/day Administration:Intravenous injection; for 9 days Result:Demonstrated statistically significant dose-dependent tumor growth inhibition.

PHA 665752 | PHA665752

Angiogenesis

c-Met/HGFR

c-Abl|c-Met|FGFR1|Flk1|RON

Cancer

——

477575-56-7

641.6078

C32H34Cl2N4O4S

>98% (HPLC)

10 mM in DMSO

O=C1NC2=C(C=C(S(=O)(CC3=C(Cl)C=CC=C3Cl)=O)C=C2)/C1=C/C4=C(C)C(C(N5[C@@H](CN6CCCC6)CCC5)=O)=C(C)N4

2H-Indol-2-one, 5-[[(2,6-dichlorophenyl)methyl]sulfonyl]-3-[[3,5-dimethyl-4-[[(2R)-2-(1-pyrrolidinylmethyl)-1-pyrrolidinyl]carbonyl]-1H-pyrrol-2-yl]methylene]-1,3-dihydro-, (3Z)-

(-20℃)

With Ice Pack

≥ 2 years