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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Cited by 47 Publications

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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 MmKyS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHLyTolKSzVyPUCuNVI{PzVizszN NWLRcJZtW0GQR1XS
LB2241-RCC M4XJPGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Mn;jTWM2OD1yLkG1O|AzKM7:TR?= MU\TRW5ITVJ?
KINGS-1 NFnvXXZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MV\JR|UxRTBwM{W5NVEh|ryP MWDTRW5ITVJ?
ALL-PO NEKzVGxIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NIjtNFdKSzVyPUCuPFEzPzdizszN NVi3TndCW0GQR1XS
SK-LMS-1 MYHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MUnJR|UxRTBwOEm4OFYh|ryP MYTTRW5ITVJ?
MV-4-11 M3fneWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUToS5ZmUUN3ME2xMlI6PDdizszN MUfTRW5ITVJ?
SUP-T1 NYHFdFhMT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M{LHUWlEPTB;Mj6xN|k3PCEQvF2= NInMPVhUSU6JRWK=
MRK-nu-1 NGHC[Y9Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXXJR|UxRTJwNECwOVYh|ryP NISxcJlUSU6JRWK=
ES1 NFzBc3BIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVHFOGxnUUN3ME2zMlM1QDZ4IN88US=> NV\EW4sxW0GQR1XS
NOS-1 NF\FdVlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NIG3SZFKSzVyPUSuN|k5PjdizszN M2Pm[nNCVkeHUh?=
KM12 M4DRfmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1O4Z2lEPTB;ND60NVgh|ryP NEL6NXhUSU6JRWK=
Becker NIDnZXRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NI\OT29KSzVyPUWuNlQ3PiEQvF2= NYPyRmF5W0GQR1XS
NCI-SNU-1 MkLWS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MVzJR|UxRTVwNkO3N|Mh|ryP Ml3FV2FPT0WU
EW-22 MnqzS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Mn;RTWM2OD15LkezOlE1KM7:TR?= MnrFV2FPT0WU
ES6 MlnGS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NXrYO4xuUUN3ME23MlgyQTVizszN MVrTRW5ITVJ?
A498 MnP3S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MkjpTWM2OD16LkK4OFQ3KM7:TR?= NFLreIlUSU6JRWK=
EW-16 MlLHS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3Hi[WlEPTB;OT62OVQ{KM7:TR?= NXmyfYdXW0GQR1XS
CTV-1 NYrUVVc4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXL5SHRxUUN3ME25Mlg2ODJ2IN88US=> NX\RNoN6W0GQR1XS
ETK-1 MUTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1TpdWlEPTB;MUCuNlk{OSEQvF2= NX7odZJQW0GQR1XS
NCI-H1395 MXPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYTJR|UxRTFyLkiwNlQh|ryP MV;TRW5ITVJ?
DOHH-2 NFLke|FIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1nzdWlEPTB;MUCuPVI3PCEQvF2= NHLndFhUSU6JRWK=
GI-1 NY\QOVZZT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MVjJR|UxRTFzLki1PVYh|ryP MoHLV2FPT0WU
HT-144 NF24SYdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MojUTWM2OD1zND6yNVY{KM7:TR?= NYjUcFh2W0GQR1XS
ES5 M1vnRWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NIDobGxKSzVyPUG0MlQ3PyEQvF2= M2\MNXNCVkeHUh?=
NALM-6 MW\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NIr2fFNKSzVyPUG1MlIyQTZizszN M2rLeXNCVkeHUh?=
KNS-81-FD NUL2clg5T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnG1TWM2OD1zNT61PFQ6KM7:TR?= M4fRfnNCVkeHUh?=
TE-15 M4PLVWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3;rVGlEPTB;MU[uOVc4OSEQvF2= MVnTRW5ITVJ?
SCC-15 M2XYSWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NV;OXGJiUUN3ME2xPE4{PDl6IN88US=> MkL1V2FPT0WU
EoL-1-cell M2Hj[2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MkHKTWM2OD1zOD60OVQ2KM7:TR?= NGDXcnhUSU6JRWK=
NCI-H720 MYDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MnriTWM2OD1zOD63O|Eh|ryP NHHSO3RUSU6JRWK=
NB14 NX7BdlVXT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mln5TWM2OD1zOT61OFI2KM7:TR?= MV\TRW5ITVJ?
KE-37 NFXqWHlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MV3JR|UxRTF7LkiyN|Mh|ryP NWj5fHVGW0GQR1XS
LXF-289 NWPEfI5zT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnfUTWM2OD1zOT64OlI6KM7:TR?= M{XVSXNCVkeHUh?=
RPMI-8402 Mlv1S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NVT1PIZxUUN3ME2yNE4{OjZ7IN88US=> M4\k[XNCVkeHUh?=
SK-N-DZ M1z2OWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NWfrdYpZUUN3ME2yNU4zOTNzIN88US=> MkD0V2FPT0WU
ACN M2D5V2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFT0RmRKSzVyPUKyMlI1QTdizszN M2P3[3NCVkeHUh?=
TE-11 MVHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NGT5RmxKSzVyPUK2MlA3QSEQvF2= M{TwW3NCVkeHUh?=
COLO-800 M1rlPWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NI\V[VlKSzVyPUK3MlE4KM7:TR?= M3u3PXNCVkeHUh?=
MOLT-13 MVPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MWjJR|UxRTJ5LkG4OFch|ryP NWnWUVN3W0GQR1XS
697 Ml\CS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NXu5c|ZpUUN3ME2yPE44PjN|IN88US=> NWrQXmVYW0GQR1XS
VA-ES-BJ MUDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MY\JR|UxRTJ7LkO3Nlkh|ryP NXfscnM1W0GQR1XS
EW-13 NFPR[XdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHjQU5pKSzVyPUK5MlUxPDVizszN NX;kWm1FW0GQR1XS
NB7 MVTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYfJR|UxRTN{LkK2OlUh|ryP NVnVc3hoW0GQR1XS
MONO-MAC-6 NVPTdGdtT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M2rkbWlEPTB;M{KuPFc6PSEQvF2= MkXhV2FPT0WU
SW962 M3y3eWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NEnhUJBKSzVyPUOzMlQ2OTNizszN M3LaUnNCVkeHUh?=
KS-1 M4f6e2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NVnx[3J5UUN3ME2zN{46PDhzIN88US=> NWLqXWZMW0GQR1XS
KU812 M1Xpe2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVfJR|UxRTN2LkW3NFIh|ryP NYfnW4drW0GQR1XS
IMR-5 MVPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3vUVWlEPTB;M{euOFMyQCEQvF2= MUfTRW5ITVJ?
BC-1 NY\He4F{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NULrNVA{UUN3ME2zPE4xOzNizszN M13Qe3NCVkeHUh?=
NCI-H510A NXm4NGVKT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXvwPGJ{UUN3ME2zPE4zODN{IN88US=> NXvvVnFvW0GQR1XS
EW-18 MXLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHrqe25KSzVyPUSwMlg{ODNizszN MUXTRW5ITVJ?
CCRF-CEM M3zLeWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4P4XWlEPTB;NEKuNlc6PyEQvF2= NGTWeWpUSU6JRWK=
HH MmDwS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M4fpeWlEPTB;NEOuOVA3QSEQvF2= Mk\hV2FPT0WU
NCI-H2171 M2TLO2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MYDJR|UxRTR4LkCyO|Ih|ryP MmnRV2FPT0WU
LC-2-ad MoLMS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFfKTZpKSzVyPUS5MlE1OTNizszN MUnTRW5ITVJ?

... 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]
- Collapse

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]
- Collapse
  • 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
  • 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 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

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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

Tel: +1-832-582-8158 Ext:3

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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