PHA-665752

Catalog No.S1070

PHA-665752 Chemical Structure

Molecular Weight(MW): 641.61

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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5 Customer Reviews

  • A, SCID mice bearing established HCC827/GR tumor cell xenografts were treated with each drug. The length and width of the tumors were measured at the days indicated and tumor volumes were calculated. The bars represent mean tumor volume ?SD. B, immunohistochemical staining for Ki-67 and TUNEL, as described in Materials and Methods. Quantitative data for proliferation and apoptotic indices are shown as Ki-67+ cells (left) and TUNEL+ cells (right). *, P < 0.01 and **, P < 0.001 for the combination of gefitinib plus NPS-1034 or gefitinib plus PHA-665752 versus either the control or drug alone.

    Cancer Res 2014 74, 253-62. PHA-665752 purchased from Selleck.

    A, representative Western blot analyses of samples obtained from NSCLC cells exposed to 1 umol/L erlotinib or PHA-665,752 for 6 hours. Levels of total and phosphorylated forms of EGFR, MET, and HER3. B, representative Western blot analyses of samples obtained as described in A showing the levels of EGFR downstream signaling mediators. Protein samples obtained from untreated and treated cells were separated by SDS-PAGE and immunoblotted with each antibody. Tubulin served to ensure equal loading.

    Clin Cancer Res 2014 20, 4806-15. PHA-665752 purchased from Selleck.

  • PHA-665752 increases the radiosensitivity and reverses the radioresistance induced by HGF in NPC cells. Radiosensitization induced by PHA-665752 is accompanied by the persistence of the c-H2AX foci. Representative immunofluorescence micrographs of the c-H2AX foci formation in PHA-665752 (1 uM), HGF (20 ng/ml), IR and their combination groups. The micrographs were taken at x 400 magnification.

    Biochem Biophys Res Commun 2014 449(1), 49-54. PHA-665752 purchased from Selleck.

    Radiosensitization induced by PHA-665752 is accompanied by the persistence of the γ-H2AX foci. (Top) Representative immunofluorescence micrographs of the γ-H2AX foci formation in PHA-665752 (1 uM), HGF (20 ng/ml), IR and their combination groups. The micrographs were taken at x400 magnification. (Bottom) The median number of the γ-H2AX foci per cell. The bars indicate the SD. ∗P < 0.01 compared with the IR alone group.

    Biochem Biophys Res Commun 2014 449, 49-54. PHA-665752 purchased from Selleck.

  • Western blot analysis of p-c-Met and c-Met. 0-100μM PHA665752 was added.

     

     

    Dr. Zhang of Tianjin Medical University. PHA-665752 purchased from Selleck.

Purity & Quality Control

Choose Selective c-Met Inhibitors

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Notes:

2. For more details, such as half maximal inhibitory concentrations (IC50s) and working concentrations of each inhibitor, please click on the link of the inhibitor of interest.
3. "+" indicates inhibitory effect. Increased inhibition is marked by a higher "+" designation.
4. Orange "√" refers to compounds which do inhibitory effects on the related isoform, but without specific value.

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)
c-Abl [1]
(Cell-free assay)
FGFR1 [1]
(Cell-free assay)
9 nM 68 nM 200 nM 1.4 μM 3 μM
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 MWPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NH;1WXNKSzVyPUCuNVI{PzVizszN NWnYUXpQW0GQR1XS
LB2241-RCC M2OyWGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Mn;kTWM2OD1yLkG1O|AzKM7:TR?= M3:1OHNCVkeHUh?=
KINGS-1 NYDtdlhRT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NFTyfVZKSzVyPUCuN|U6OTFizszN MYjTRW5ITVJ?
ALL-PO MXHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mn\sTWM2OD1yLkixNlc4KM7:TR?= NEPyV2VUSU6JRWK=
SK-LMS-1 NWDlbXp7T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NHj5ZVhKSzVyPUCuPFk5PDZizszN NX[wUYtqW0GQR1XS
MV-4-11 M2XtcGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MXfJR|UxRTFwMkm0O{DPxE1? M{fJWHNCVkeHUh?=
SUP-T1 NVr4TmtrT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M{j6WmlEPTB;Mj6xN|k3PCEQvF2= MWnTRW5ITVJ?
MRK-nu-1 M4LUTWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NVfycVRFUUN3ME2yMlQxODV4IN88US=> NYe4WmVkW0GQR1XS
ES1 NF;p[mhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFO1VmlKSzVyPUOuN|Q5PjZizszN NUj5V5JyW0GQR1XS
NOS-1 NEHON2tIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NIjoe4RKSzVyPUSuN|k5PjdizszN M3v2bXNCVkeHUh?=
KM12 MmPyS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MX\JR|UxRTRwNEG4JO69VQ>? NHPabVdUSU6JRWK=
Becker NVP6eXp7T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXO2ZYx6UUN3ME21MlI1PjZizszN M1nxZXNCVkeHUh?=
NCI-SNU-1 M2XXWGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MW\JR|UxRTVwNkO3N|Mh|ryP NVjZfJpLW0GQR1XS
EW-22 MUjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MW\JR|UxRTdwN{O2NVQh|ryP NWr5cHZjW0GQR1XS
ES6 NUG2RXZ7T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NILBWpZKSzVyPUeuPFE6PSEQvF2= MWjTRW5ITVJ?
A498 MUPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NUnFU5hkUUN3ME24MlI5PDR4IN88US=> MW\TRW5ITVJ?
EW-16 M4i1WGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MYfJR|UxRTlwNkW0N{DPxE1? Ml;JV2FPT0WU
CTV-1 Ml3oS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MXTJR|UxRTlwOEWwNlQh|ryP NXLw[IxxW0GQR1XS
ETK-1 Ml3VS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MY\JR|UxRTFyLkK5N|Eh|ryP M2HHVHNCVkeHUh?=
NCI-H1395 M4HrOWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NVHweI9SUUN3ME2xNE45ODJ2IN88US=> MV;TRW5ITVJ?
DOHH-2 NFH5ZmpIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NWS3fJo1UUN3ME2xNE46OjZ2IN88US=> MnHPV2FPT0WU
GI-1 MmP4S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NEnEfVNKSzVyPUGxMlg2QTZizszN NEjBVXlUSU6JRWK=
HT-144 NF32T|FIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MofkTWM2OD1zND6yNVY{KM7:TR?= MUDTRW5ITVJ?
ES5 NF\LWpBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFHqeGNKSzVyPUG0MlQ3PyEQvF2= NFe2cW9USU6JRWK=
NALM-6 Mn\HS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Ml;nTWM2OD1zNT6yNVk3KM7:TR?= NIPhbopUSU6JRWK=
KNS-81-FD MV3Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3nDN2lEPTB;MUWuOVg1QSEQvF2= NEjKNlJUSU6JRWK=
TE-15 NX\rSpVxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXW4SohsUUN3ME2xOk42PzdzIN88US=> MY\TRW5ITVJ?
SCC-15 M2rre2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYT5RpRvUUN3ME2xPE4{PDl6IN88US=> MYXTRW5ITVJ?
EoL-1-cell M2fHRmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3TaU2lEPTB;MUiuOFU1PSEQvF2= NWriPVFTW0GQR1XS
NCI-H720 M1fhcWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MmHCTWM2OD1zOD63O|Eh|ryP MVXTRW5ITVJ?
NB14 MnLiS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3LxSWlEPTB;MUmuOVQzPSEQvF2= MmrhV2FPT0WU
KE-37 MnLWS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MomwTWM2OD1zOT64NlM{KM7:TR?= NHL3ZVhUSU6JRWK=
LXF-289 MVnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYjJR|UxRTF7Lki2Nlkh|ryP NV\oeHVtW0GQR1XS
RPMI-8402 MWHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWDHVIV4UUN3ME2yNE4{OjZ7IN88US=> MU\TRW5ITVJ?
SK-N-DZ MXXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MWPJR|UxRTJzLkKxN|Eh|ryP NUjXZ3luW0GQR1XS
ACN MWTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NH:1NllKSzVyPUKyMlI1QTdizszN NH:4RnVUSU6JRWK=
TE-11 NF[0ZWtIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MYXJR|UxRTJ4LkC2PUDPxE1? NYPCOWhxW0GQR1XS
COLO-800 NFXmbGRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHf2Z|VKSzVyPUK3MlE4KM7:TR?= MkLLV2FPT0WU
MOLT-13 MoSxS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NXXkb49DUUN3ME2yO{4yQDR5IN88US=> NED1ZnlUSU6JRWK=
697 MnLuS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NV;6WVR7UUN3ME2yPE44PjN|IN88US=> MWHTRW5ITVJ?
VA-ES-BJ NYG3PFl6T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1j6TWlEPTB;MkmuN|czQSEQvF2= M{\LbHNCVkeHUh?=
EW-13 NYn5S2RpT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NIXub2tKSzVyPUK5MlUxPDVizszN NWfV[2dHW0GQR1XS
NB7 NWrBXlRYT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M3jUUmlEPTB;M{KuNlY3PSEQvF2= MlLiV2FPT0WU
MONO-MAC-6 M3LTN2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NGLqPY9KSzVyPUOyMlg4QTVizszN NIewPItUSU6JRWK=
SW962 MWnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MV3JR|UxRTN|LkS1NVMh|ryP NWnofHZ3W0GQR1XS
KS-1 NFH4ZWtIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MoOwTWM2OD1|Mz65OFgyKM7:TR?= M{X4bnNCVkeHUh?=
KU812 Mm\jS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3y2Z2lEPTB;M{SuOVcxOiEQvF2= MkT1V2FPT0WU
IMR-5 NWrHcIVOT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NEDVcoJKSzVyPUO3MlQ{OThizszN NELuZ25USU6JRWK=
BC-1 M2\Gc2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYflS|NFUUN3ME2zPE4xOzNizszN MXrTRW5ITVJ?
NCI-H510A MkLiS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NYjkflBvUUN3ME2zPE4zODN{IN88US=> MVHTRW5ITVJ?
EW-18 MmXYS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Mn30TWM2OD12MD64N|A{KM7:TR?= MXjTRW5ITVJ?
CCRF-CEM MYHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M4m4TGlEPTB;NEKuNlc6PyEQvF2= M2m2RXNCVkeHUh?=
HH NXHjb3NET3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWXJR|UxRTR|LkWwOlkh|ryP MWTTRW5ITVJ?
NCI-H2171 NXe4eZFDT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M{TMVGlEPTB;NE[uNFI4OiEQvF2= M3\mXXNCVkeHUh?=
LC-2-ad NYDLcYUzT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NGDI[GlKSzVyPUS5MlE1OTNizszN M3HYfHNCVkeHUh?=

... Click to View More Cell Line Experimental Data

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
+ Expand

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
+ Expand
  • 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
+ Expand
  • Animal Models: Female athymic mice (nu/nu) bearing S114 or GTL-16 tumor xenografts
  • Formulation: Formulated in vehicle (L-lactate (pH 4.8) and 10% polyethylene glycol)
  • 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 <1 mg/mL
Ethanol <1 mg/mL
In vivo 2% DMSO+castor oil 5mg/mL

* 1 mg/ml means slightly soluble or insoluble.
* 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

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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.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID