PHA-665752

For research use only.

Catalog No.S1070

70 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 70 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 NFXGV2dIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M{iyNWlEPTB;MD6xNlM4PSEQvF2= MYfTRW5ITVJ?
LB2241-RCC NWjQV5BMT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MUnJR|UxRTBwMUW3NFIh|ryP M1zWVHNCVkeHUh?=
KINGS-1 M1\nfmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NIHT[YJKSzVyPUCuN|U6OTFizszN M{fZbXNCVkeHUh?=
ALL-PO NHTUeoxIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NU\pUXhYUUN3ME2wMlgyOjd5IN88US=> Ml\aV2FPT0WU
SK-LMS-1 MV;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M2TiOmlEPTB;MD64PVg1PiEQvF2= Mn7kV2FPT0WU
MV-4-11 M1Lye2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlfWTWM2OD1zLkK5OFch|ryP NEfJOZlUSU6JRWK=
SUP-T1 M37udWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3Hr[2lEPTB;Mj6xN|k3PCEQvF2= NX;2XG04W0GQR1XS
MRK-nu-1 NI\PS|NIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXvJR|UxRTJwNECwOVYh|ryP NELXR4FUSU6JRWK=
ES1 NXjxe2FUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NGe0S5ZKSzVyPUOuN|Q5PjZizszN M3TVUXNCVkeHUh?=
NOS-1 NVy4eJlsT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MVjJR|UxRTRwM{m4Olch|ryP NXPxVmQ4W0GQR1XS
KM12 MlPtS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MVzJR|UxRTRwNEG4JO69VQ>? NGHoSnVUSU6JRWK=
Becker NVH0[IJlT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MV\JR|UxRTVwMkS2OkDPxE1? MmrVV2FPT0WU
NCI-SNU-1 M4rld2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlTBTWM2OD13Lk[zO|M{KM7:TR?= Mo[yV2FPT0WU
EW-22 NEC0cZFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NV:5b5dFUUN3ME23Mlc{PjF2IN88US=> NInz[VNUSU6JRWK=
ES6 NVfRSZhCT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1;UWWlEPTB;Nz64NVk2KM7:TR?= MYfTRW5ITVJ?
A498 Mk\rS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHXtUmFKSzVyPUiuNlg1PDZizszN NVnSb|dmW0GQR1XS
EW-16 NHSyV5lIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXLJR|UxRTlwNkW0N{DPxE1? NVjZcJY2W0GQR1XS
CTV-1 M3[5T2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUHDS2JKUUN3ME25Mlg2ODJ2IN88US=> NXzxWWY6W0GQR1XS
ETK-1 MWDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MlG2TWM2OD1zMD6yPVMyKM7:TR?= MVXTRW5ITVJ?
NCI-H1395 Mn:yS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3fqbGlEPTB;MUCuPFAzPCEQvF2= NIixWoZUSU6JRWK=
DOHH-2 NEH0cYxIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MmjETWM2OD1zMD65NlY1KM7:TR?= M4e2O3NCVkeHUh?=
GI-1 MWHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYrJR|UxRTFzLki1PVYh|ryP M2HPO3NCVkeHUh?=
HT-144 MljQS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NYC4bZBjUUN3ME2xOE4zOTZ|IN88US=> NX\1c3FZW0GQR1XS
ES5 M4HvUmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NEjlZZVKSzVyPUG0MlQ3PyEQvF2= NFLFW45USU6JRWK=
NALM-6 NXrVdZFCT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVO4O2EzUUN3ME2xOU4zOTl4IN88US=> M{\z[XNCVkeHUh?=
KNS-81-FD NIO5SmFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVzCR5Q4UUN3ME2xOU42QDR7IN88US=> M1yxS3NCVkeHUh?=
TE-15 M{DhfWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MWPJR|UxRTF4LkW3O|Eh|ryP MVPTRW5ITVJ?
SCC-15 Mn\yS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MnLqTWM2OD1zOD6zOFk5KM7:TR?= NUX1b3FXW0GQR1XS
EoL-1-cell NVzDWWxFT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVv1Z5BvUUN3ME2xPE41PTR3IN88US=> NUHhb|h5W0GQR1XS
NCI-H720 NE\mSmhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= Ml7PTWM2OD1zOD63O|Eh|ryP NIjxdIpUSU6JRWK=
NB14 NH;aSFZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXXJR|UxRTF7LkW0NlUh|ryP MXjTRW5ITVJ?
KE-37 MWjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MojYTWM2OD1zOT64NlM{KM7:TR?= NYS1UWZXW0GQR1XS
LXF-289 NV7N[WhpT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NHnvdXZKSzVyPUG5Mlg3OjlizszN M3\uRnNCVkeHUh?=
RPMI-8402 NVi4PW1UT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXPlW|NQUUN3ME2yNE4{OjZ7IN88US=> MVzTRW5ITVJ?
SK-N-DZ NUXhb4ZIT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NWPEdllqUUN3ME2yNU4zOTNzIN88US=> NFrRPI1USU6JRWK=
ACN MXvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M4H0bmlEPTB;MkKuNlQ6PyEQvF2= M1m1[nNCVkeHUh?=
TE-11 M1;0Rmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1O3dmlEPTB;Mk[uNFY6KM7:TR?= MnHQV2FPT0WU
COLO-800 NH3qSGJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= Mnf6TWM2OD1{Nz6xO{DPxE1? NFzyWotUSU6JRWK=
MOLT-13 NVzQSot5T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M4L1fWlEPTB;MkeuNVg1PyEQvF2= NWq5N49DW0GQR1XS
697 M1HT[2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NW\re5JEUUN3ME2yPE44PjN|IN88US=> MVzTRW5ITVJ?
VA-ES-BJ NIG0[pJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MoToTWM2OD1{OT6zO|I6KM7:TR?= NXrZO4lzW0GQR1XS
EW-13 NE\XenBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NIDqeFZKSzVyPUK5MlUxPDVizszN MVjTRW5ITVJ?
NB7 MkK5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MonuTWM2OD1|Mj6yOlY2KM7:TR?= NV65ZZNXW0GQR1XS
MONO-MAC-6 Mmn1S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MWTJR|UxRTN{Lki3PVUh|ryP M3qzRXNCVkeHUh?=
SW962 NWrkfI9lT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NX3WbohxUUN3ME2zN{41PTF|IN88US=> M{nUdHNCVkeHUh?=
KS-1 MoLUS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Mkm0TWM2OD1|Mz65OFgyKM7:TR?= M{\sUnNCVkeHUh?=
KU812 NWHZRoV4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mn3uTWM2OD1|ND61O|AzKM7:TR?= MX3TRW5ITVJ?
IMR-5 NUm0cWJRT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MUjJR|UxRTN5LkSzNVgh|ryP MYjTRW5ITVJ?
BC-1 NWPH[JVKT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MVTJR|UxRTN6LkCzN{DPxE1? MkLBV2FPT0WU
NCI-H510A NVfQcolGT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnnBTWM2OD1|OD6yNFMzKM7:TR?= NUT0c41kW0GQR1XS
EW-18 NEfZe2xIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NEDCUGRKSzVyPUSwMlg{ODNizszN NY\HWpdNW0GQR1XS
CCRF-CEM MXjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NGnYWJJKSzVyPUSyMlI4QTdizszN NGPufItUSU6JRWK=
HH NWnvS2xCT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NYXaU|BCUUN3ME20N{42ODZ7IN88US=> Mo\yV2FPT0WU
NCI-H2171 M3W2PGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1XlPWlEPTB;NE[uNFI4OiEQvF2= MV7TRW5ITVJ?
LC-2-ad NVHYeHZNT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M17WUGlEPTB;NEmuNVQyOyEQvF2= NGHQVGxUSU6JRWK=

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
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.

IDO; 

PubMed: 27082119     


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

25226813 27082119
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]
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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.

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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