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

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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 Mkj0S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MW\JR|UxRTBwMUKzO|Uh|ryP MkHkV2FPT0WU
LB2241-RCC Ml33S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M2ey[mlEPTB;MD6xOVcxOiEQvF2= MVvTRW5ITVJ?
KINGS-1 MniwS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NEn0PXJKSzVyPUCuN|U6OTFizszN NXHDcVVTW0GQR1XS
ALL-PO M2X0[mdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MoP5TWM2OD1yLkixNlc4KM7:TR?= M4PjcHNCVkeHUh?=
SK-LMS-1 M3\UWWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4H6[GlEPTB;MD64PVg1PiEQvF2= NGjIWFhUSU6JRWK=
MV-4-11 NXHxW4xHT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NGXpbY9KSzVyPUGuNlk1PyEQvF2= Moq2V2FPT0WU
SUP-T1 M3;xUWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MmXITWM2OD1{LkGzPVY1KM7:TR?= NIroRnVUSU6JRWK=
MRK-nu-1 NVr5[W9wT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NInNXpZKSzVyPUKuOFAxPTZizszN MmPLV2FPT0WU
ES1 MkThS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3PIXWlEPTB;Mz6zOFg3PiEQvF2= M1vPcHNCVkeHUh?=
NOS-1 NI\lZmhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVXJR|UxRTRwM{m4Olch|ryP NV3pdWlLW0GQR1XS
KM12 Ml\3S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MoKwTWM2OD12LkSxPEDPxE1? M{\hPXNCVkeHUh?=
Becker Mn:3S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWj1W4t{UUN3ME21MlI1PjZizszN M{LL[XNCVkeHUh?=
NCI-SNU-1 NXfke4RYT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NHjKTnpKSzVyPUWuOlM4OzNizszN MlXJV2FPT0WU
EW-22 MXXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1HMOmlEPTB;Nz63N|YyPCEQvF2= MUXTRW5ITVJ?
ES6 NGO5OmpIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1XJTWlEPTB;Nz64NVk2KM7:TR?= MnvSV2FPT0WU
A498 NYG1Opp2T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NFTIWolKSzVyPUiuNlg1PDZizszN M3f2[HNCVkeHUh?=
EW-16 NHzYR5pIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NUK2VJJ4UUN3ME25MlY2PDNizszN NHK1UlRUSU6JRWK=
CTV-1 NHjGeIlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MV7JR|UxRTlwOEWwNlQh|ryP NFrPcpFUSU6JRWK=
ETK-1 NY\UVHpET3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M4\DSmlEPTB;MUCuNlk{OSEQvF2= NIHZbmtUSU6JRWK=
NCI-H1395 MnHIS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NYj4OWlWUUN3ME2xNE45ODJ2IN88US=> M3Xoc3NCVkeHUh?=
DOHH-2 NUf2RYxST3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MYPJR|UxRTFyLkmyOlQh|ryP MYHTRW5ITVJ?
GI-1 MXvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MVTJR|UxRTFzLki1PVYh|ryP Ml7mV2FPT0WU
HT-144 NHTx[WFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVTJR|UxRTF2LkKxOlMh|ryP MlHEV2FPT0WU
ES5 Ml[yS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MXfJR|UxRTF2LkS2O{DPxE1? Mlf2V2FPT0WU
NALM-6 MkTlS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NUXBcFBKUUN3ME2xOU4zOTl4IN88US=> NEjKT2RUSU6JRWK=
KNS-81-FD NI\BcmZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NX7pTYdoUUN3ME2xOU42QDR7IN88US=> NH3jOmxUSU6JRWK=
TE-15 NXznfGN3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mn;OTWM2OD1zNj61O|cyKM7:TR?= M1m4R3NCVkeHUh?=
SCC-15 MX;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{PyeWlEPTB;MUiuN|Q6QCEQvF2= M1rFWXNCVkeHUh?=
EoL-1-cell MkHOS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MULJR|UxRTF6LkS1OFUh|ryP MUPTRW5ITVJ?
NCI-H720 MYTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NETKbFJKSzVyPUG4Mlc4OSEQvF2= NWrENYxWW0GQR1XS
NB14 MnLIS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NV\1dHlTUUN3ME2xPU42PDJ3IN88US=> NFzDPHBUSU6JRWK=
KE-37 MXLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M2DLNGlEPTB;MUmuPFI{OyEQvF2= NXnNRmFyW0GQR1XS
LXF-289 MX3Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYfJR|UxRTF7Lki2Nlkh|ryP MXrTRW5ITVJ?
RPMI-8402 M2nIVmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFXVfJpKSzVyPUKwMlMzPjlizszN NV\rWm5UW0GQR1XS
SK-N-DZ MkTxS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3nuVmlEPTB;MkGuNlE{OSEQvF2= NGHRclZUSU6JRWK=
ACN NEnhOldIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXzJR|UxRTJ{LkK0PVch|ryP MUDTRW5ITVJ?
TE-11 NWT1cphVT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MlTSTWM2OD1{Nj6wOlkh|ryP MVvTRW5ITVJ?
COLO-800 M3vPbmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MWnJR|UxRTJ5LkG3JO69VQ>? MXjTRW5ITVJ?
MOLT-13 MUHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NUXIUXNwUUN3ME2yO{4yQDR5IN88US=> MXvTRW5ITVJ?
697 M4G2VGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MoTqTWM2OD1{OD63OlM{KM7:TR?= M3jtXXNCVkeHUh?=
VA-ES-BJ NHm1V49Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3jISGlEPTB;MkmuN|czQSEQvF2= NIDhTlhUSU6JRWK=
EW-13 NEj2dHVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NWDZcoZJUUN3ME2yPU42ODR3IN88US=> NVK3WWY6W0GQR1XS
NB7 NYD6bZFCT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MlfjTWM2OD1|Mj6yOlY2KM7:TR?= NXjTVHpiW0GQR1XS
MONO-MAC-6 NE\aRYpIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NInVVZBKSzVyPUOyMlg4QTVizszN MYLTRW5ITVJ?
SW962 NX7TWGV{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXv4bXp6UUN3ME2zN{41PTF|IN88US=> NInW[XVUSU6JRWK=
KS-1 MVHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MWrJR|UxRTN|Lkm0PFEh|ryP NI\lZnZUSU6JRWK=
KU812 MlTNS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1vSWWlEPTB;M{SuOVcxOiEQvF2= Ml\XV2FPT0WU
IMR-5 M135fWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M{\aVmlEPTB;M{euOFMyQCEQvF2= MVPTRW5ITVJ?
BC-1 NXXXb2JWT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NFz0dXhKSzVyPUO4MlA{OyEQvF2= NY[4O4kzW0GQR1XS
NCI-H510A NHzuS4FIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M17SdGlEPTB;M{iuNlA{OiEQvF2= MoHUV2FPT0WU
EW-18 NWja[|V4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NWfEeYh2UUN3ME20NE45OzB|IN88US=> NV3hR29JW0GQR1XS
CCRF-CEM M3\0PGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Ml3YTWM2OD12Mj6yO|k4KM7:TR?= NFK5dJdUSU6JRWK=
HH M3jLXWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2nNS2lEPTB;NEOuOVA3QSEQvF2= M1e2SXNCVkeHUh?=
NCI-H2171 NUL5[GlST3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1T6XmlEPTB;NE[uNFI4OiEQvF2= NVzMPFA2W0GQR1XS
LC-2-ad M3;RSmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Mlq0TWM2OD12OT6xOFE{KM7:TR?= MYXTRW5ITVJ?

... 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