PHA-665752

Catalog No.S1070

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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PHA-665752 Chemical Structure

PHA-665752 Chemical Structure
Molecular Weight: 641.61

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Product Information

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  • Research Area
  • Inhibition Profile
  • PHA-665752 Mechanism

Product Description

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)

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IC50 9 nM 68 nM 200 nM 1.4 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 LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
NCI-SNU-5M3LoeGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7MoXnTWM2OD1yLkGyN|c2KM7:TR?=M1LmNXNCVkeHUh?=
LB2241-RCCMXTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?MkS0TWM2OD1yLkG1O|AzKM7:TR?=M1PFcHNCVkeHUh?=
KINGS-1NU\MPYFmT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NW\aOY12UUN3ME2wMlM2QTFzIN88US=>MVnTRW5ITVJ?
ALL-PONYLzRm1QT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NV60coZ[UUN3ME2wMlgyOjd5IN88US=>NX73fm1WW0GQR1XS
SK-LMS-1NY\XN21IT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=MoDnTWM2OD1yLki5PFQ3KM7:TR?=MYjTRW5ITVJ?
MV-4-11MWHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?NFy5S|RKSzVyPUGuNlk1PyEQvF2=M4fUTnNCVkeHUh?=
SUP-T1NUn5WlZWT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=M2D2V2lEPTB;Mj6xN|k3PCEQvF2=M2PXV3NCVkeHUh?=
MRK-nu-1Mnu5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?MmfmTWM2OD1{LkSwNFU3KM7:TR?=Mkf1V2FPT0WU
ES1NYm5No5KT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NELv[|hKSzVyPUOuN|Q5PjZizszNM1TkeXNCVkeHUh?=
NOS-1MVXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?NX3iXldlUUN3ME20MlM6QDZ5IN88US=>M3fPWXNCVkeHUh?=
KM12MoeyS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?MkjNTWM2OD12LkSxPEDPxE1?MoWxV2FPT0WU
BeckerNY\ETY9HT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=MnewTWM2OD13LkK0OlYh|ryPNXG3RndlW0GQR1XS
NCI-SNU-1MoHJS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?M4i0dGlEPTB;NT62N|c{OyEQvF2=MVzTRW5ITVJ?
EW-22NE\5NIFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=MX3JR|UxRTdwN{O2NVQh|ryPM2jKSXNCVkeHUh?=
ES6MVnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?NUi5bZcxUUN3ME23MlgyQTVizszNNVrYc28zW0GQR1XS
A498Mlz5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?M3GxRWlEPTB;OD6yPFQ1PiEQvF2=MXvTRW5ITVJ?
EW-16M3XoPGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7NVXzfmpNUUN3ME25MlY2PDNizszNNIDQRZdUSU6JRWK=
CTV-1M3rzc2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7MYfJR|UxRTlwOEWwNlQh|ryPM{nlTHNCVkeHUh?=
ETK-1NXu5OGl[T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=M1rRb2lEPTB;MUCuNlk{OSEQvF2=M13CcHNCVkeHUh?=
NCI-H1395MV;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?NVrUS2U3UUN3ME2xNE45ODJ2IN88US=>M{ftfHNCVkeHUh?=
DOHH-2NIXrdnVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NFjjc25KSzVyPUGwMlkzPjRizszNMnjTV2FPT0WU
GI-1MWLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?Ml;nTWM2OD1zMT64OVk3KM7:TR?=M3fvbnNCVkeHUh?=
HT-144MlzRS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?M4HEOWlEPTB;MUSuNlE3OyEQvF2=NUPKWZI5W0GQR1XS
ES5NG[5bnNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NYjw[IlRUUN3ME2xOE41PjdizszNMXLTRW5ITVJ?
NALM-6M2\BdGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7NIf0Z5FKSzVyPUG1MlIyQTZizszNM{[zVnNCVkeHUh?=
KNS-81-FDNHvzVFNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NYPXPINMUUN3ME2xOU42QDR7IN88US=>M1nLTnNCVkeHUh?=
TE-15NGDwXW5Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NUPFfWt2UUN3ME2xOk42PzdzIN88US=>MmC0V2FPT0WU
SCC-15NH\oXYdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=MYPJR|UxRTF6LkO0PVgh|ryPNIjpc4ZUSU6JRWK=
EoL-1-cellNUPQRnlmT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=MXvJR|UxRTF6LkS1OFUh|ryPMnjrV2FPT0WU
NCI-H720NVziZYdUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NFmzSGRKSzVyPUG4Mlc4OSEQvF2=MoKyV2FPT0WU
NB14M37wTWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7MVLJR|UxRTF7LkW0NlUh|ryPM3PRNnNCVkeHUh?=
KE-37M1\qVGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7NFTOZYpKSzVyPUG5MlgzOzNizszNNHrLZoNUSU6JRWK=
LXF-289MoX5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?MYTJR|UxRTF7Lki2Nlkh|ryPNF\kR5JUSU6JRWK=
RPMI-8402NVnOR5RIT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=MWHJR|UxRTJyLkOyOlkh|ryPNFPQbohUSU6JRWK=
SK-N-DZMXrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?Ml3xTWM2OD1{MT6yNVMyKM7:TR?=MnTnV2FPT0WU
ACNMXXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?MnXnTWM2OD1{Mj6yOFk4KM7:TR?=NH;SXXpUSU6JRWK=
TE-11M3;oZWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7NYfk[mFwUUN3ME2yOk4xPjlizszNM1nBW3NCVkeHUh?=
COLO-800M4T5XWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7NHfHfXVKSzVyPUK3MlE4KM7:TR?=M1m0WHNCVkeHUh?=
MOLT-13NGfqTINIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=M4C5WWlEPTB;MkeuNVg1PyEQvF2=M2j1OnNCVkeHUh?=
697M{W2WWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7Mm\wTWM2OD1{OD63OlM{KM7:TR?=MWfTRW5ITVJ?
VA-ES-BJNYex[ngzT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NHfTO4VKSzVyPUK5MlM4OjlizszNNGW5XXZUSU6JRWK=
EW-13MljlS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?NWi5b4t6UUN3ME2yPU42ODR3IN88US=>NHPOfZRUSU6JRWK=
NB7MmWzS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?MV\JR|UxRTN{LkK2OlUh|ryPNVTndW92W0GQR1XS
MONO-MAC-6M4DCWWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7MWDJR|UxRTN{Lki3PVUh|ryPNHHhZmZUSU6JRWK=
SW962NYDaVnpET3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=MmTITWM2OD1|Mz60OVE{KM7:TR?=NFvVWodUSU6JRWK=
KS-1NIDJb|lIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=M4LROGlEPTB;M{OuPVQ5OSEQvF2=NVrObHp2W0GQR1XS
KU812MYnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?MkfqTWM2OD1|ND61O|AzKM7:TR?=MXnTRW5ITVJ?
IMR-5MUHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?M4XZVWlEPTB;M{euOFMyQCEQvF2=MWPTRW5ITVJ?
BC-1NF3pT|ZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NWHMfJhmUUN3ME2zPE4xOzNizszNMl3yV2FPT0WU
NCI-H510AMUTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?M130SWlEPTB;M{iuNlA{OiEQvF2=NIP0W2VUSU6JRWK=
EW-18M3q0[Wdzd3e2aDDJcohq[mm2aX;uJGF{e2G7M1e0TmlEPTB;NECuPFMxOyEQvF2=MkPVV2FPT0WU
CCRF-CEMNW\1OXZyT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NG\VZYRKSzVyPUSyMlI4QTdizszNM2DGUXNCVkeHUh?=
HHNVnmTWlnT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NHnEWpFKSzVyPUSzMlUxPjlizszNMn;WV2FPT0WU
NCI-H2171M3O4WWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7NWLLNphqUUN3ME20Ok4xOjd{IN88US=>NXfTUJJlW0GQR1XS
LC-2-adNEXkZ3pIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NFTSfHZKSzVyPUS5MlE1OTNizszNM2Xrc3NCVkeHUh?=

... 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]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

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 Assay: [1]

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.

Animal Study: [1]

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.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Christensen JG, et al. Cancer Res, 2003, 63(21), 7345-7355.

[2] Ma PC, et al. Clin Cancer Res, 2005, 11(6), 2312-2319.

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Chemical Information

Download PHA-665752 SDF
Molecular Weight (MW) 641.61
Formula

C32H34Cl2N4O4S

CAS No. 477575-56-7
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 128 mg/mL (199.49 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
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 Name (R,Z)-5-(2,6-dichlorobenzylsulfonyl)-3-((3,5-dimethyl-4-(2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl)-1H-pyrrol-2-yl)methylene)indolin-2-one

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.

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

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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