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PHA-665752

Name: PHA-665752
Brand: Selleck Chemicals
SKU: S1070
Rating: 5 (95 reviews)

Catalog No.S1070 Purity:99.91%

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.

PHA-665752 Chemical Structure

CAS No. 477575-56-7

Purity & Quality Control

Batch: Purity: 99.91%

99.91

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Signaling Pathway

c-Met Signaling Pathway

Cell Data

Cell Lines	Assay Type	Activity Description	PMID
NCI-SNU-5	Growth Inhibition Assay	IC50=0.12375 μM	SANGER
LB2241-RCC	Growth Inhibition Assay	IC50=0.15702 μM	SANGER
KINGS-1	Growth Inhibition Assay	IC50=0.35911 μM	SANGER
ALL-PO	Growth Inhibition Assay	IC50=0.81277 μM	SANGER
SK-LMS-1	Growth Inhibition Assay	IC50=0.89846 μM	SANGER
MV-4-11	Growth Inhibition Assay	IC50=1.2947 μM	SANGER
SUP-T1	Growth Inhibition Assay	IC50=2.13964 μM	SANGER
MRK-nu-1	Growth Inhibition Assay	IC50=2.40056 μM	SANGER
ES1	Growth Inhibition Assay	IC50=3.34866 μM	SANGER
NOS-1	Growth Inhibition Assay	IC50=4.39867 μM	SANGER
KM12	Growth Inhibition Assay	IC50=4.418 μM	SANGER
Becker	Growth Inhibition Assay	IC50=5.2466 μM	SANGER
NCI-SNU-1	Growth Inhibition Assay	IC50=5.63733 μM	SANGER
EW-22	Growth Inhibition Assay	IC50=7.73614 μM	SANGER
ES6	Growth Inhibition Assay	IC50=7.8195 μM	SANGER
A498	Growth Inhibition Assay	IC50=8.28446 μM	SANGER
EW-16	Growth Inhibition Assay	IC50=9.6543 μM	SANGER
CTV-1	Growth Inhibition Assay	IC50=9.85024 μM	SANGER
ETK-1	Growth Inhibition Assay	IC50=10.2931 μM	SANGER
NCI-H1395	Growth Inhibition Assay	IC50=10.8024 μM	SANGER
DOHH-2	Growth Inhibition Assay	IC50=10.9264 μM	SANGER
GI-1	Growth Inhibition Assay	IC50=11.8596 μM	SANGER
HT-144	Growth Inhibition Assay	IC50=14.2163 μM	SANGER
ES5	Growth Inhibition Assay	IC50=14.467 μM	SANGER
NALM-6	Growth Inhibition Assay	IC50=15.2196 μM	SANGER
KNS-81-FD	Growth Inhibition Assay	IC50=15.5849 μM	SANGER
TE-15	Growth Inhibition Assay	IC50=16.5771 μM	SANGER
SCC-15	Growth Inhibition Assay	IC50=18.3498 μM	SANGER
EoL-1-cell	Growth Inhibition Assay	IC50=18.4545 μM	SANGER
NCI-H720	Growth Inhibition Assay	IC50=18.771 μM	SANGER
NB14	Growth Inhibition Assay	IC50=19.5425 μM	SANGER
KE-37	Growth Inhibition Assay	IC50=19.8233 μM	SANGER
LXF-289	Growth Inhibition Assay	IC50=19.8629 μM	SANGER
RPMI-8402	Growth Inhibition Assay	IC50=20.3269 μM	SANGER
SK-N-DZ	Growth Inhibition Assay	IC50=21.2131 μM	SANGER
ACN	Growth Inhibition Assay	IC50=22.2497 μM	SANGER
TE-11	Growth Inhibition Assay	IC50=26.069 μM	SANGER
COLO-800	Growth Inhibition Assay	IC50=27.17 μM	SANGER
MOLT-13	Growth Inhibition Assay	IC50=27.1847 μM	SANGER
697	Growth Inhibition Assay	IC50=28.7633 μM	SANGER
VA-ES-BJ	Growth Inhibition Assay	IC50=29.3729 μM	SANGER
EW-13	Growth Inhibition Assay	IC50=29.5045 μM	SANGER
NB7	Growth Inhibition Assay	IC50=32.2665 μM	SANGER
MONO-MAC-6	Growth Inhibition Assay	IC50=32.8795 μM	SANGER
SW962	Growth Inhibition Assay	IC50=33.4513 μM	SANGER
KS-1	Growth Inhibition Assay	IC50=33.9481 μM	SANGER
KU812	Growth Inhibition Assay	IC50=34.5702 μM	SANGER
IMR-5	Growth Inhibition Assay	IC50=37.4318 μM	SANGER
BC-1	Growth Inhibition Assay	IC50=38.033 μM	SANGER
NCI-H510A	Growth Inhibition Assay	IC50=38.2032 μM	SANGER
EW-18	Growth Inhibition Assay	IC50=40.8303 μM	SANGER
CCRF-CEM	Growth Inhibition Assay	IC50=42.2797 μM	SANGER
HH	Growth Inhibition Assay	IC50=43.5069 μM	SANGER
NCI-H2171	Growth Inhibition Assay	IC50=46.0272 μM	SANGER
LC-2-ad	Growth Inhibition Assay	IC50=49.1413 μM	SANGER
Click to View More Cell Line Experimental Data

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
In vitro	PHA-665752 significantly inhibits c-Met kinase activity with K_i 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]
Kinase Assay	In vitro enzyme assay
Kinase 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	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.
Experimental Result Images	Methods	Biomarkers	Images	PMID
	Western blot	IDO p-Met / Met / p-Akt / Akt / p-ERK / ERK		27082119
	Growth inhibition assay	Cell proliferation		20603611

In Vivo
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]
Animal Research	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.

References

Chemical Information & Solubility

Molecular Weight	641.61	Formula	C₃₂H₃₄Cl₂N₄O₄S
CAS No.	477575-56-7	SDF	Download PHA-665752 SDF
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
Storage (From the date of receipt)	3 years-20°Cpowder	Storage of Stock Solutions Aliquot the stock solutions to avoid repeated freeze-thaw cycles	1 year-80°Cin solvent
Storage (From the date of receipt)	3 years-20°Cpowder		1 month-20°Cin solvent

In vitro
Batch:

DMSO : 128 mg/mL ( (199.49 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 10 mg/mL

Water : Insoluble

Molecular Weight Calculator

In vivo Batch: Add solvents to the product individually and in order.				In vivo Formulation Calculator
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution	5% DMSO 1 95% corn oil Validated by Selleck labs. Should you need adjustments to this formulation, contact our sales team for custom testing.	0.460mg/ml (0.72mM)	Taking the 1 mL working solution as an example, add 50 μL of clarified DMSO stock solution of 9.2 mg/ml to 950 μL of corn oil, mix evenly to clarify it, and prepare the working solution for immediate use!
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

Preparing Stock Solutions

Molarity Calculator

Mass	Concentration	Volume	Molecular Weight
=	×	×

Dilution Calculator Molecular Weight Calculator

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)

Dosage: mg/kg Average weight of animals: g Dosing volume per animal:μL Number of animals:

Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Calculation results:

Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

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
If you have any other enquiries, please leave a message.

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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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