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 MX\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MVnJR|UxRTBwMUKzO|Uh|ryP MWPTRW5ITVJ?
LB2241-RCC MWjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NXzTNWN6UUN3ME2wMlE2PzB{IN88US=> NFWwdmVUSU6JRWK=
KINGS-1 NWfQ[ZlkT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NX32eGlRUUN3ME2wMlM2QTFzIN88US=> MYPTRW5ITVJ?
ALL-PO NFTDNodIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NGDkPVdKSzVyPUCuPFEzPzdizszN NYnJSFcyW0GQR1XS
SK-LMS-1 M{\tSGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MWPJR|UxRTBwOEm4OFYh|ryP NV7TNoVyW0GQR1XS
MV-4-11 NXHRPJZIT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NYrLUoZ4UUN3ME2xMlI6PDdizszN M2G4NHNCVkeHUh?=
SUP-T1 Mn3TS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlfKTWM2OD1{LkGzPVY1KM7:TR?= MlHHV2FPT0WU
MRK-nu-1 Mm\qS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MXLJR|UxRTJwNECwOVYh|ryP MX7TRW5ITVJ?
ES1 M1T2bWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHm4NYlKSzVyPUOuN|Q5PjZizszN M2XZUXNCVkeHUh?=
NOS-1 M3zndmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NH73[ZRKSzVyPUSuN|k5PjdizszN M2\uenNCVkeHUh?=
KM12 MVTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{fM[mlEPTB;ND60NVgh|ryP NIjqcFlUSU6JRWK=
Becker NWfnepd{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NIX2R|NKSzVyPUWuNlQ3PiEQvF2= NH3kToNUSU6JRWK=
NCI-SNU-1 MmjSS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MWXJR|UxRTVwNkO3N|Mh|ryP NISxW2lUSU6JRWK=
EW-22 Mon6S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHL0[IdKSzVyPUeuO|M3OTRizszN M3PrXXNCVkeHUh?=
ES6 MkHpS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWjqTIFWUUN3ME23MlgyQTVizszN NWPGXVN7W0GQR1XS
A498 MmLIS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHTzTY1KSzVyPUiuNlg1PDZizszN M3zqfHNCVkeHUh?=
EW-16 M2\DRmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M{jVeGlEPTB;OT62OVQ{KM7:TR?= NUfh[3dwW0GQR1XS
CTV-1 NHHpR2RIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVjJR|UxRTlwOEWwNlQh|ryP MlO2V2FPT0WU
ETK-1 MWjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NGPQSY1KSzVyPUGwMlI6OzFizszN MmfqV2FPT0WU
NCI-H1395 MV\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M4rDcWlEPTB;MUCuPFAzPCEQvF2= NV[2dmxGW0GQR1XS
DOHH-2 M3npNGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NXjsTlJIUUN3ME2xNE46OjZ2IN88US=> M4P4eXNCVkeHUh?=
GI-1 NUf4OZI3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NF;3UohKSzVyPUGxMlg2QTZizszN Mkf3V2FPT0WU
HT-144 MYLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHjpb5FKSzVyPUG0MlIyPjNizszN NEPEeFdUSU6JRWK=
ES5 NVTLeYZNT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnnUTWM2OD1zND60Olch|ryP NIXaUnVUSU6JRWK=
NALM-6 NX;XRWdPT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NUfpTVRuUUN3ME2xOU4zOTl4IN88US=> M2\DNHNCVkeHUh?=
KNS-81-FD MV;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NUnleJc3UUN3ME2xOU42QDR7IN88US=> NW\qXY41W0GQR1XS
TE-15 NWfIc294T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NW\6W2c5UUN3ME2xOk42PzdzIN88US=> M4PCVHNCVkeHUh?=
SCC-15 M3[yZWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M{Sye2lEPTB;MUiuN|Q6QCEQvF2= M2nTO3NCVkeHUh?=
EoL-1-cell MoXWS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NIG5[IpKSzVyPUG4MlQ2PDVizszN NIqxO5VUSU6JRWK=
NCI-H720 M3vhUWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFrFN2ZKSzVyPUG4Mlc4OSEQvF2= NU\oTIZ1W0GQR1XS
NB14 MnjoS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M2DjSGlEPTB;MUmuOVQzPSEQvF2= NH2xPVJUSU6JRWK=
KE-37 NFfSU4ZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M33Hd2lEPTB;MUmuPFI{OyEQvF2= MmP4V2FPT0WU
LXF-289 NV3mOXNYT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M{DQc2lEPTB;MUmuPFYzQSEQvF2= NWTIU3dyW0GQR1XS
RPMI-8402 NIixN41Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3nKOmlEPTB;MkCuN|I3QSEQvF2= NWLyWG44W0GQR1XS
SK-N-DZ M3XKV2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MkDnTWM2OD1{MT6yNVMyKM7:TR?= NX75PXVoW0GQR1XS
ACN NUHDenRCT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnTyTWM2OD1{Mj6yOFk4KM7:TR?= M4Dk[HNCVkeHUh?=
TE-11 NYPI[4l[T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MUXJR|UxRTJ4LkC2PUDPxE1? Mm[yV2FPT0WU
COLO-800 NV3Bepg4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NFLtbVVKSzVyPUK3MlE4KM7:TR?= MXTTRW5ITVJ?
MOLT-13 NVvvcHhTT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NV\iemNUUUN3ME2yO{4yQDR5IN88US=> MnvCV2FPT0WU
697 M{fO[Wdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlzRTWM2OD1{OD63OlM{KM7:TR?= M4eyXnNCVkeHUh?=
VA-ES-BJ MlzWS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NX\QN4UzUUN3ME2yPU4{PzJ7IN88US=> M4\zbXNCVkeHUh?=
EW-13 NUfRWnJXT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NV7OSmtnUUN3ME2yPU42ODR3IN88US=> NWLPOmszW0GQR1XS
NB7 NYn2ZYlET3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M{PEdWlEPTB;M{KuNlY3PSEQvF2= NGLCTpJUSU6JRWK=
MONO-MAC-6 MlvuS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NITlVlNKSzVyPUOyMlg4QTVizszN Ml3SV2FPT0WU
SW962 MYfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NFHvU2xKSzVyPUOzMlQ2OTNizszN MV7TRW5ITVJ?
KS-1 MYXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Ml3ETWM2OD1|Mz65OFgyKM7:TR?= M13vXnNCVkeHUh?=
KU812 NHf0NFZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NGDhTlJKSzVyPUO0MlU4ODJizszN M1Xh[HNCVkeHUh?=
IMR-5 MX;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NH7qTYNKSzVyPUO3MlQ{OThizszN MX3TRW5ITVJ?
BC-1 MXvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWLpOVJXUUN3ME2zPE4xOzNizszN MoPEV2FPT0WU
NCI-H510A MkXNS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlvKTWM2OD1|OD6yNFMzKM7:TR?= MXnTRW5ITVJ?
EW-18 MUXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MkjUTWM2OD12MD64N|A{KM7:TR?= MVHTRW5ITVJ?
CCRF-CEM MorMS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1rCWmlEPTB;NEKuNlc6PyEQvF2= NWr4XW5CW0GQR1XS
HH NHTt[pdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NW\2RWdqUUN3ME20N{42ODZ7IN88US=> MYjTRW5ITVJ?
NCI-H2171 NHHXb5BIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVTJR|UxRTR4LkCyO|Ih|ryP Ml3JV2FPT0WU
LC-2-ad NF[5dJVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NWfUNnkyUUN3ME20PU4yPDF|IN88US=> M2jGdHNCVkeHUh?=

... 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:[1]
+ 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:[1]
+ 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:[1]
+ 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