PHA-665752

SKU: orb1224991

Description

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.

Research Area

Metabolism Research

Key Properties

• CAS Number: 477575-56-7
• MW: 641.6078
• Purity: >98% (HPLC)
• Formula: C₃₂H₃₄Cl₂N₄O₄S
• SMILES: 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
• Target: c-Met/HGFR
• Solubility: 10 mM in DMSO

Bioactivity

• In Vivo:
  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.
• In Vitro:
  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 Assay Cell 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.

Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

PHA 665752 | PHA665752

Quick Database Links

Gene Symbol

c-Met/HGFR