PHA-665752

For research use only.

Catalog No.S1070

62 publications

PHA-665752 Chemical Structure

CAS No. 477575-56-7

PHA-665752 is a potent, selective and ATP-competitive c-Met inhibitor with IC50 of 9 nM in cell-free assays, >50-fold selectivity for c-Met than RTKs or STKs.

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Selleck's PHA-665752 has been cited by 62 publications

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Choose Selective c-Met Inhibitors

Biological Activity

Description PHA-665752 is a potent, selective and ATP-competitive c-Met inhibitor with IC50 of 9 nM in cell-free assays, >50-fold selectivity for c-Met than RTKs or STKs.
Targets
c-Met [1]
(Cell-free assay)
RON [1]
(Cell-free assay)
Flk1 [1]
(Cell-free assay)
9 nM 68 nM 200 nM
In vitro

PHA-665752 significantly inhibits c-Met kinase activity with Ki of 4 nM, and exhibits >50-fold selectivity for c-Met compared with various tyrosine and serine-threonine kinases. PHA-665752 potently inhibits the HGF-stimulated c-Met autophosphorylation with IC50 of 25-50 nM. PHA-665752 also significantly blocks HGF- and c-Met-dependent functions such as cell motility and cell proliferation with IC50 of 40-50 nM and 18-42 nM, respectively. In addition, PHA-665752 potently 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. [1] PHA-665752 inhibits cell growth in TPR-MET-transformed BaF3 cells with IC50 of <60 nM, and inhibits constitutive cell motility and migration by 92.5% at 0.2 μM. Inhibition of c-Met by PHA665752 (0.2 μM) also induces cell apoptosis of 33.1% and G1 cell cycle arrest with cells in G1 phase increasing from 42.4% to 77.0%. PHA665752 can cooperate with rapamycin to inhibit cell growth of TPR-MET-transformed BaF3 cells and non-small cell lung cancer H441 cells. [2]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
NCI-SNU-5 NGXY[3JIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M4m4OmlEPTB;MD6xNlM4PSEQvF2= M1G4THNCVkeHUh?=
LB2241-RCC NYP0UFFnT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NI[1XG1KSzVyPUCuNVU4ODJizszN M{H5b3NCVkeHUh?=
KINGS-1 NH\WZoxIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MlLnTWM2OD1yLkO1PVEyKM7:TR?= MojwV2FPT0WU
ALL-PO NX;ETJpjT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXXZOm5{UUN3ME2wMlgyOjd5IN88US=> MWLTRW5ITVJ?
SK-LMS-1 MUfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MXfJR|UxRTBwOEm4OFYh|ryP M2nCU3NCVkeHUh?=
MV-4-11 NYXoZ4RUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MXPJR|UxRTFwMkm0O{DPxE1? M2riUXNCVkeHUh?=
SUP-T1 MUTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHLQPHZKSzVyPUKuNVM6PjRizszN M3XqVXNCVkeHUh?=
MRK-nu-1 M1\Lcmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NXfD[JBLUUN3ME2yMlQxODV4IN88US=> Ml7lV2FPT0WU
ES1 NXO2dmdYT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXLjSmloUUN3ME2zMlM1QDZ4IN88US=> M{LrT3NCVkeHUh?=
NOS-1 M1LTc2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NIXEVYhKSzVyPUSuN|k5PjdizszN M162T3NCVkeHUh?=
KM12 MV;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1fhT2lEPTB;ND60NVgh|ryP NX;xc4NtW0GQR1XS
Becker NVjCcI9ZT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NEfm[I9KSzVyPUWuNlQ3PiEQvF2= NWrjPHZjW0GQR1XS
NCI-SNU-1 MYXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MlLBTWM2OD13Lk[zO|M{KM7:TR?= Mnz3V2FPT0WU
EW-22 MoPNS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFvZenBKSzVyPUeuO|M3OTRizszN MXPTRW5ITVJ?
ES6 MXnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NEfRV4JKSzVyPUeuPFE6PSEQvF2= MnXKV2FPT0WU
A498 NUXFT4JtT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NYH6c4U6UUN3ME24MlI5PDR4IN88US=> MlnJV2FPT0WU
EW-16 M{HCfmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2nH[mlEPTB;OT62OVQ{KM7:TR?= M2fXe3NCVkeHUh?=
CTV-1 NVjNZ4tlT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MVTJR|UxRTlwOEWwNlQh|ryP MoP3V2FPT0WU
ETK-1 MoXkS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NE\vbmtKSzVyPUGwMlI6OzFizszN M2fETHNCVkeHUh?=
NCI-H1395 M37JSWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3e0O2lEPTB;MUCuPFAzPCEQvF2= MVXTRW5ITVJ?
DOHH-2 MYfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MUnJR|UxRTFyLkmyOlQh|ryP NUX0TG56W0GQR1XS
GI-1 M2TpW2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYXVelY6UUN3ME2xNU45PTl4IN88US=> MV7TRW5ITVJ?
HT-144 M4HNeGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2DaSGlEPTB;MUSuNlE3OyEQvF2= MnPyV2FPT0WU
ES5 MUPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M2LQ[GlEPTB;MUSuOFY4KM7:TR?= MUDTRW5ITVJ?
NALM-6 MmLxS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NVPmWW52UUN3ME2xOU4zOTl4IN88US=> NUnSbmxMW0GQR1XS
KNS-81-FD MWnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NULxclRQUUN3ME2xOU42QDR7IN88US=> NYXXc5dZW0GQR1XS
TE-15 MV;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NEnxTWdKSzVyPUG2MlU4PzFizszN M{\1fXNCVkeHUh?=
SCC-15 MWLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M2j3R2lEPTB;MUiuN|Q6QCEQvF2= NXnyPWhZW0GQR1XS
EoL-1-cell Ml\pS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHGxR|RKSzVyPUG4MlQ2PDVizszN MoG0V2FPT0WU
NCI-H720 NHHyfIVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NV3TXIR1UUN3ME2xPE44PzFizszN NUjseVEyW0GQR1XS
NB14 MWjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3Hq[GlEPTB;MUmuOVQzPSEQvF2= NIHyOmhUSU6JRWK=
KE-37 Mle5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NEn0c5dKSzVyPUG5MlgzOzNizszN MVzTRW5ITVJ?
LXF-289 MlftS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M{\jT2lEPTB;MUmuPFYzQSEQvF2= NWTPVmJ3W0GQR1XS
RPMI-8402 MlfMS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3;oTmlEPTB;MkCuN|I3QSEQvF2= MX\TRW5ITVJ?
SK-N-DZ MkX2S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MX\JR|UxRTJzLkKxN|Eh|ryP MnXNV2FPT0WU
ACN NWLObW9[T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MXTJR|UxRTJ{LkK0PVch|ryP NVvpN3FoW0GQR1XS
TE-11 MknGS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NXrJTlBqUUN3ME2yOk4xPjlizszN MnjTV2FPT0WU
COLO-800 NEDXcXZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NUHYcpE4UUN3ME2yO{4yPyEQvF2= MX3TRW5ITVJ?
MOLT-13 MXzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NIj5R45KSzVyPUK3MlE5PDdizszN MlvCV2FPT0WU
697 NIrlTYJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVOwTGR3UUN3ME2yPE44PjN|IN88US=> MnXTV2FPT0WU
VA-ES-BJ NVHwb2xkT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M4qwUWlEPTB;MkmuN|czQSEQvF2= MVjTRW5ITVJ?
EW-13 MVHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NV7p[nBCUUN3ME2yPU42ODR3IN88US=> MojyV2FPT0WU
NB7 NF7mZ5hIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3PHe2lEPTB;M{KuNlY3PSEQvF2= MXTTRW5ITVJ?
MONO-MAC-6 MnHOS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M2D2SWlEPTB;M{KuPFc6PSEQvF2= M3;TfnNCVkeHUh?=
SW962 MVjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1PXSmlEPTB;M{OuOFUyOyEQvF2= NV7jT2RMW0GQR1XS
KS-1 M1fXRWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NIK1[JhKSzVyPUOzMlk1QDFizszN M3HQdHNCVkeHUh?=
KU812 NVXKR4dTT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MX7JR|UxRTN2LkW3NFIh|ryP NIH1OYpUSU6JRWK=
IMR-5 M1fI[mdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MoTXTWM2OD1|Nz60N|E5KM7:TR?= NEm2[nhUSU6JRWK=
BC-1 MlPkS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlzjTWM2OD1|OD6wN|Mh|ryP M{DUVXNCVkeHUh?=
NCI-H510A MYLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M2flfGlEPTB;M{iuNlA{OiEQvF2= MmnFV2FPT0WU
EW-18 MofJS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MYLJR|UxRTRyLkizNFMh|ryP MkW5V2FPT0WU
CCRF-CEM NULx[JZLT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MmTNTWM2OD12Mj6yO|k4KM7:TR?= M4CzU3NCVkeHUh?=
HH NX3pRlVlT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NFrXcGJKSzVyPUSzMlUxPjlizszN M1HoVnNCVkeHUh?=
NCI-H2171 MVfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Ml3LTWM2OD12Nj6wNlczKM7:TR?= MnjWV2FPT0WU
LC-2-ad NWWxOGFqT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M3nxTGlEPTB;NEmuNVQyOyEQvF2= M{fyV3NCVkeHUh?=

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
IDO; 

PubMed: 27082119     


PHA-665752 inhibited both c-Met phosphorylation and IDO expression of SKOV-3 cells in a concentration-dependent manner.

p-Met / Met / p-Akt / Akt / p-ERK / ERK ; 

PubMed: 25226813     


HCC827 GR6 cells were treated for 6 h with increasing concentrations of tivantinib or PHA-665752. Cell lysates were immunoblotted to detect indicated proteins. PHA-665752 partially inhibits MET and ERK1/2 phosphorylation but not AKT. Tivantinib did not inhibit MET phosphorylation or downstream signaling.

27082119 25226813
Growth inhibition assay
Cell proliferation ; 

PubMed: 20603611     


Cell proliferation was evaluated at fixed times after the addition of HGF (50 ng/ml) +/− PHA-665752 (d) at different concentrations in 2% FBS-containing medium. PHA-665752 showed a marked reduction in cell numbers starting from 24 h at micromolar concentrations (5 and 10 μ), whereas lower concentrations did not exert a significant reduction of proliferation with respect to the control. 

20603611
In vivo Administration of PHA-665752 induces a dose-dependent tumor growth inhibition of S114 xenografts by 20 %, 39% and 68%, at dose of 7.5, 15, and 30 mg/kg/day, respectively. [1] PHA665752 treatment significantly reduces the tumor growth of NCI-H69, NCI-H441 and A549 in mouse xenografts by 99%, 75%, and 59%, respectively. PHA665752 also significantly inhibits angiogenesis by >85%, due to decreasing the production of vascular endothelial growth factor and increasing the production of the angiogenesis inhibitor thrombospondin-1. [3]

Protocol

Kinase Assay:[1]
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In vitro enzyme assay:

The c-Met kinase domain GST-fusion protein is used for the c-Met assay. The IC50 value of PHA-665752 for the inhibition of c-Met is based on phosphorylation of kinase peptide substrates or poly-glu-tyr in the presence of ATP and divalent cation (MgCl2 or MnCl2 10-20 mM). The linear range (i.e., the time period over which the rate remains equivalent to the initial rate) is determined for c-Met, and the kinetic measurement and IC50 determination are performed within this range.
Cell Research:[1]
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  • Cell lines: S114, GTL-16, NCI-H441, and BxPC-3
  • Concentrations: Dissolved in DMSO, final concentrations ~10 μM
  • Incubation Time: 18, or 72 hours
  • Method: For proliferation assays, cells are grown in medium with 0.1% FBS for 48 hours after which they are treated with various concentrations of PHA-665752 in HGF (50 ng/mL) in a medium containing 2% FBS. After 18 hours, cells are incubated with BrdUrd for 1 hour, fixed, and stained with anti-BrdUrd peroxidase-conjugated antibody, and plates are read at 630 nm. For apoptosis assays, cells are grown in medium with 2% FBS in presence and absence of HGF (50 ng/mL) and various concentrations of PHA-665752 for 72 hours. After 72 hours, a mixture containing ethidium bromide and acridine orange is added, and apoptotic cells (bright orange cells or cell fragments) are counted by fluorescence microscopy.
    (Only for Reference)
Animal Research:[1]
- Collapse
  • Animal Models: Female athymic mice (nu/nu) bearing S114 or GTL-16 tumor xenografts
  • Dosages: ~30 mg/kg/day
  • Administration: Injection via bolus i.v.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 128 mg/mL (199.49 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
2% DMSO+castor oil
For best results, use promptly after mixing.
5mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 641.61
Formula

C32H34Cl2N4O4S

CAS No. 477575-56-7
Storage powder
in solvent
Synonyms N/A
Smiles CC1=C(NC(=C1C(=O)N2CCCC2CN3CCCC3)C)C=C4C5=C(C=CC(=C5)S(=O)(=O)CC6=C(C=CC=C6Cl)Cl)NC4=O

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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Frequently Asked Questions

  • Question 1:

    I need to use S1070 for intraperitoneal application in mice. Could you tell me the solvent you use, please?

  • Answer:

    The highest concentration of PHA-665752 (S1070) in 4% DMSO+30% PEG 300+5% Tween 80+ddH2O is 5mg/ml. If you want to get higher concentration, the concentration of DMSO and PEG will be higher. For example, it can be dissolved in 8% DMSO+50% PEG 300+5% Tween 80+ddH2O at 10mg/ml clearly.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID