PHA-665752

For research use only.

Catalog No.S1070

58 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 58 publications

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Choose Selective c-Met Inhibitors

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 NEDpfnJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXvJR|UxRTBwMUKzO|Uh|ryP MU\TRW5ITVJ?
LB2241-RCC MmLCS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFHBO5lKSzVyPUCuNVU4ODJizszN NInUVohUSU6JRWK=
KINGS-1 NHjXfXNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NE\vTVBKSzVyPUCuN|U6OTFizszN M3e0T3NCVkeHUh?=
ALL-PO NVHhSGRUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXXLU|h7UUN3ME2wMlgyOjd5IN88US=> MVfTRW5ITVJ?
SK-LMS-1 NGLZUG1Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MmLRTWM2OD1yLki5PFQ3KM7:TR?= NFm0TFRUSU6JRWK=
MV-4-11 NUnQfos{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MUXJR|UxRTFwMkm0O{DPxE1? NFLrOVNUSU6JRWK=
SUP-T1 MXjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MofMTWM2OD1{LkGzPVY1KM7:TR?= NIf1PFJUSU6JRWK=
MRK-nu-1 M{Dkc2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MWDJR|UxRTJwNECwOVYh|ryP MofwV2FPT0WU
ES1 M3H1[Wdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUnVTWQ4UUN3ME2zMlM1QDZ4IN88US=> MYTTRW5ITVJ?
NOS-1 MW\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M2\I[mlEPTB;ND6zPVg3PyEQvF2= NGDDcoRUSU6JRWK=
KM12 MXLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3HufmlEPTB;ND60NVgh|ryP M2j2OHNCVkeHUh?=
Becker MUnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NXTJRW5lUUN3ME21MlI1PjZizszN MXHTRW5ITVJ?
NCI-SNU-1 MlzjS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MVjJR|UxRTVwNkO3N|Mh|ryP NXPsZW4{W0GQR1XS
EW-22 NXi3bJVIT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NGP5XIJKSzVyPUeuO|M3OTRizszN MmXWV2FPT0WU
ES6 MV;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{nrW2lEPTB;Nz64NVk2KM7:TR?= NIHpbmdUSU6JRWK=
A498 NUDJN4lNT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1\5UGlEPTB;OD6yPFQ1PiEQvF2= MlfwV2FPT0WU
EW-16 NX;nR2s4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M37qO2lEPTB;OT62OVQ{KM7:TR?= NVi3NFdsW0GQR1XS
CTV-1 NIDJUVVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFrVVJZKSzVyPUmuPFUxOjRizszN NFXQO4VUSU6JRWK=
ETK-1 NHviOFdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2rI[WlEPTB;MUCuNlk{OSEQvF2= NHjaV5pUSU6JRWK=
NCI-H1395 NYXyOlhYT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1TpRWlEPTB;MUCuPFAzPCEQvF2= MXnTRW5ITVJ?
DOHH-2 NXrl[ol3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NEL1U5dKSzVyPUGwMlkzPjRizszN MWDTRW5ITVJ?
GI-1 NE\FcHJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2jBcmlEPTB;MUGuPFU6PiEQvF2= MXzTRW5ITVJ?
HT-144 NXjPOGI2T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NUWyfXkxUUN3ME2xOE4zOTZ|IN88US=> M{DETXNCVkeHUh?=
ES5 NYXnWXZZT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWXJR|UxRTF2LkS2O{DPxE1? M{P0RnNCVkeHUh?=
NALM-6 NGjRUmFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NX32fphpUUN3ME2xOU4zOTl4IN88US=> NVLKV5VRW0GQR1XS
KNS-81-FD MY\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NUDIV2tnUUN3ME2xOU42QDR7IN88US=> NIDIboZUSU6JRWK=
TE-15 NUTj[YljT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NUHrTYhPUUN3ME2xOk42PzdzIN88US=> MUHTRW5ITVJ?
SCC-15 NF;RV3BIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M4nMeWlEPTB;MUiuN|Q6QCEQvF2= MnXWV2FPT0WU
EoL-1-cell NV;MUZFkT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NWe0R|NZUUN3ME2xPE41PTR3IN88US=> NXzPW2ZnW0GQR1XS
NCI-H720 MXTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{n4fWlEPTB;MUiuO|cyKM7:TR?= NXvTbJB5W0GQR1XS
NB14 Mn3wS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NET0N3RKSzVyPUG5MlU1OjVizszN MXXTRW5ITVJ?
KE-37 M1z4Omdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Mmi5TWM2OD1zOT64NlM{KM7:TR?= M3jiRXNCVkeHUh?=
LXF-289 MkPxS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHzCZpFKSzVyPUG5Mlg3OjlizszN MYHTRW5ITVJ?
RPMI-8402 Mkj3S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NXyyVG4yUUN3ME2yNE4{OjZ7IN88US=> M1nSRXNCVkeHUh?=
SK-N-DZ M4DSbGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M33pZmlEPTB;MkGuNlE{OSEQvF2= MVzTRW5ITVJ?
ACN NXTV[5RiT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWHJR|UxRTJ{LkK0PVch|ryP MVXTRW5ITVJ?
TE-11 M4r4U2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NF\4OZNKSzVyPUK2MlA3QSEQvF2= Ml[2V2FPT0WU
COLO-800 NYPEN2V3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mke3TWM2OD1{Nz6xO{DPxE1? NEC0Zm1USU6JRWK=
MOLT-13 NYTUOXNbT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M3X4UmlEPTB;MkeuNVg1PyEQvF2= MUnTRW5ITVJ?
697 MV7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mo\5TWM2OD1{OD63OlM{KM7:TR?= NXu2OW12W0GQR1XS
VA-ES-BJ NGnEfnlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3S5emlEPTB;MkmuN|czQSEQvF2= NGHHbnBUSU6JRWK=
EW-13 NGXx[XFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFXxUppKSzVyPUK5MlUxPDVizszN MULTRW5ITVJ?
NB7 NVvaeYxUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MmXWTWM2OD1|Mj6yOlY2KM7:TR?= NVHJPFFbW0GQR1XS
MONO-MAC-6 MYjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MmHxTWM2OD1|Mj64O|k2KM7:TR?= NX7vOpJEW0GQR1XS
SW962 NXTWOY51T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MUTJR|UxRTN|LkS1NVMh|ryP NH[1V2RUSU6JRWK=
KS-1 MUXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NEPIWHVKSzVyPUOzMlk1QDFizszN NHPEN2FUSU6JRWK=
KU812 NUfmbHBKT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MkHwTWM2OD1|ND61O|AzKM7:TR?= M1rjNnNCVkeHUh?=
IMR-5 MWTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NEW2N2lKSzVyPUO3MlQ{OThizszN NYPiZXNOW0GQR1XS
BC-1 MnfHS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NVLGSod7UUN3ME2zPE4xOzNizszN M17ueXNCVkeHUh?=
NCI-H510A NXzMZ4NPT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NWrBfHpwUUN3ME2zPE4zODN{IN88US=> NWjDNnlLW0GQR1XS
EW-18 M2TUVmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlX2TWM2OD12MD64N|A{KM7:TR?= M4XYbXNCVkeHUh?=
CCRF-CEM MUPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NUTxTI5sUUN3ME20Nk4zPzl5IN88US=> MXjTRW5ITVJ?
HH M3PrR2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFPBbndKSzVyPUSzMlUxPjlizszN NXHuXpZjW0GQR1XS
NCI-H2171 MXvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MUTJR|UxRTR4LkCyO|Ih|ryP MorFV2FPT0WU
LC-2-ad MULHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1\qWmlEPTB;NEmuNVQyOyEQvF2= MlvnV2FPT0WU

... 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]
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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]
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  • 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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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