PF-04217903

Name: PF-04217903
Brand: Selleck Chemicals
SKU: S1094
Rating: 5 (20 reviews)

For research use only.

Catalog No.S1094

20 publications

CAS No. 956905-27-4

PF-04217903 is a selective ATP-competitive c-Met inhibitor with IC50 of 4.8 nM in A549 cell line, susceptible to oncogenic mutations (no activity to Y1230C mutant). Phase 1.

Selleck's PF-04217903 has been cited by 20 publications

Cell Chem Biol, 2019, 10.1016/j.chembiol.2019.06.003

PubMed: 31257184 ( click the link to review the publication )

Neoplasia, 2019, 22(1):1-9

PubMed: 31751859 ( click the link to review the publication )

Sci Rep, 2019, 9(1):606

PubMed: 30679640 ( click the link to review the publication )

Sci Rep, 2019, 9(1):1897

PubMed: 30760778 ( click the link to review the publication )

J Clin Invest, 2018, 128(9):4086-4097

PubMed: 29990309 ( click the link to review the publication )

J Exp Clin Cancer Res, 2018, 37(1):93

PubMed: 29712569 ( click the link to review the publication )

Invest New Drugs, 2018, 36(4):536-544

PubMed: 29188469 ( click the link to review the publication )

Immunity, 2017, 47(4):789-802

PubMed: 29045907 ( click the link to review the publication )

Cancer Discov, 2017, 7(7):750-765

PubMed: 28274958 ( click the link to review the publication )

J Clin Invest, 2016, 126(6):2181-90

PubMed: 27159396 ( click the link to review the publication )

BMC Cancer, 2016, 16:105

PubMed: 26879245 ( click the link to review the publication )

Nat Commun, 2015, 6:7174

PubMed: 26013381 ( click the link to review the publication )

Clin Cancer Res, 2015, 21(1):166-74

PubMed: 25351743 ( click the link to review the publication )

Clin Cancer Res, 2015, 1(7):1752-63

PubMed: 25762344 ( click the link to review the publication )

Hypertension, 2015, 65(3):587-93

PubMed: 25510828 ( click the link to review the publication )

Hypertension, 2015, 65(3):587-93

PubMed: ( click the link to review the publication )

Oncotarget, 2015,

PubMed: 25576915 ( click the link to review the publication )

Clin Cancer Res, 2014, 20(17):4559-73

PubMed: 24973425 ( click the link to review the publication )

PLoS One, 2013, 10.1371/journal.pone.0081275

PubMed: 24265843 ( click the link to review the publication )

Eur J Cancer, 2011, 47(8):1231-43

PubMed: 21273060 ( click the link to review the publication )

Purity & Quality Control

Choose Selective c-Met Inhibitors

Biological Activity

Description

PF-04217903 is a selective ATP-competitive c-Met inhibitor with IC50 of 4.8 nM in A549 cell line, susceptible to oncogenic mutations (no activity to Y1230C mutant). Phase 1.

Targets

c-Met ^[1]
(A549 cells)

4.8 nM

In vitro

Being more selective than staurosporine or PF-02341066, PF-04217903 displays >1000-fold selectivity for c-Met over a panel of 208 kinases, although more susceptible to oncogenic mutations of c-Met that attenuate potency than PF-02341066. In addition to WT c-Met, PF-04217903 displays similar potency to inhibit the activity of c-Met-H1094R, c-Met-R988C, and c-Met-T1010I with IC50 of 3.1 nM, 6.4 nM, and 6.7 nM, respectively, but has no inhibitory activity against c-Met-Y1230C with IC50 of >10 μM. ^[1] PF-04217903 in combination with sunitinib significantly inhibits endothelial cells, but not the tumor cells B16F1, Tib6, EL4, and LLC ^[2] PF-04217903 significantly inhibits the clonogenic growth of LXFA 526L and LXFA 1647L with IC50 values of 16 nM, and 13 nM, respectively, yielding an additive effect when in combination with cetuximab. ^[3] PF-04217903 potently inhibits c-Met-driven processes such as cell growth, motility, invasion, and morphology of a variety of tumor cells. PF-04217903 treatment (2 μM) increased cell death of GTL-16 cells, which involves the downregulation of phosphorylated 4E-BP1, ERK/MAPK associated proteins and PI3K/AKT pathway. ^[4]

Cell Data

Cell Lines	Assay Type	Concentration	Incubation Time	Formulation	Activity Description	PMID
human A549 cells	NGXab2ZHfW6ldHnvckBie3OjeR?=		M4P0TlEhcA>?		NY\le3I2SW62YXfvcol{fCCjY4Tpeol1gSCjdDDjMW1GXCC{ZXPldJRweiCrbjDoeY1idiCDNUS5JINmdGy\|IHHzd4V{e2WmIHHzJIlvcGmkaYTpc44hd2ZiYYX0c5Bpd3OyaH;yfYxifGmxbjDh[pRmeiBzIHjyJIJ6KEWOSWPBMEBKSzVyPUSgcm0>	M2faVVIzQTJ2N{O0

... Click to View More Cell Line Experimental Data

In vivo

Although unable to inhibit tumor growth in the sunitinib-sensitive B16F1 and Tib6 tumor models, the combination of PF-04217903 and sunitinib significantly inhibits tumor growth in sunitinib-resistant EL4, and LLC tumor models compared with sunitinib or PF-04217903 alone by significantly blocking vascular expansion, indicating a functional role for HGF/c-Met axis in the sunitinib-resistant tumors. ^[2]

Protocol

Kinase Assay:^[1]	- Collapse Cellular c-Met phosphorylation ELISA: A549 cells with endogenous human WT c-Met are seeded in 96-well plates in growth medium and cultured overnight. On the second day of the assay, the growth medium is replaced with serum-free medium (with 0.04% BSA). Serial dilutions of PF-04217903 are added to each well, and cells are incubated at 37 °C for 1 hour. Then 40 ng/mL HGF is added to the cells for 20 minutes. The cells are washed once with HBSS supplemented with 1 mM Na₃VO₄, and protein lysates are generated from cells using lysis buffer. Phosphorylation of c-Met is assessed by an ELISA method utilizing capture antibodies specific for c-Met and a detection antibody specific for phosphorylated tyrosine residues. Antibody-coated plates are incubated in the presence of protein lysates at 4 °C overnight and washed with 1% Tween 20 in PBS seven times. HRP-PY20 (horseradish peroxidase-conjugated anti-phosphotyrosine) is diluted 1:500 in blocking buffer and added to each plate for 30 minutes. Plates are then washed again, and TMB peroxidase substrate is added to initiate the HRP-dependent colorimetric reaction and the reaction stopped by addition of 0.09 N H₂SO₄. ELISA end points are the absorbance measured at 450 nm using a spectrophotometer. IC50 value is calculated by concentration-response curve fitting utilizing a Microsoft Excel-based four-parameter analytical met
Cell Research:^[2]	- Collapse Cell lines: B16F1, Tib6, EL4, and LLC, HUVECs and C166 cells Concentrations: Dissolved in DMSO, final concentrations ~2 μM Incubation Time: 4 days Method: Cells are treated with different concentrations PF-04217903 for 4 days. Cell proliferation is assessed by counting content of each well using a Coulter counter machine. (Only for Reference)
Animal Research:^[2]	- Collapse Animal Models: Immunodeficient nude mice (nu/nu) subcutaneously implanted with tumor cell lines B16F1, EL4, LLC, or Tib6 Dosages: 45 mg/kg Administration: Orally (Only for Reference)

References

[4] Dillon R, et al. J Proteome Res, 2011, 10(11), 5084-5094.

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Solubility (25°C)

In vitro	DMSO	5 mg/mL (13.42 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+30% PEG 300+2% Tween 80+ddH2O For best results, use promptly after mixing.	2mg/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 Download PF-04217903 SDF

Molecular Weight	372.38
Formula	C₁₉H₁₆N₈O
CAS No.	956905-27-4
Storage	3 years-20°C powder 2 years-80°C in solvent
Synonyms	N/A
Smiles	C1=CC2=C(C=CC(=C2)CN3C4=NC(=CN=C4N=N3)C5=CN(N=C5)CCO)N=C1

In vivo Formulation Calculator (Clear solution)

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

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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.

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.

Bio Calculators

Molarity Calculator

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This equation is commonly abbreviated as: C1V1 = C2V2 ( Input Output )

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The Serial Dilution Calculator Equation

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Computed Result

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Molecular Weight Calculator

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Tip: Chemical formula is case sensitive. C10H16N2O2 c10h16n2o2

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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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c-Met Signaling Pathway Map

c-Met Inhibitors with Unique Features

Non-specific c-Met Inhibitor

BMS-777607 : C-Met, IC50=3.9 nM；Axl, IC50=1.1 nM; Ron, IC50=1.8 nM; Tyro3, IC50=4.3 nM.
Most Potent c-Met Inhibitor

INCB28060 : C-Met, IC50=0.13 nM.
FDA-approved c-Met Inhibitor

Crizotinib (PF-02341066) : Approved by FDA for non-small cell lung carcinoma (NSCLC).
Newest c-Met Inhibitor

EMD 1214063 ^New : Potent and selective c-Met inhibitor with IC50 of 4 nM, >200-fold selective for c-Met than IRAK4, TrkA, Axl, IRAK1, and Mer.

Related c-Met Products

NPS-1034 ^New

NPS-1034 is a dual Met (c-Met)/Axl inhibitor with IC50 of 48 nM and 10.3 nM, respectively.
Erlotinib ^New

Erlotinib (CP358774, NSC 718781, OSI-774) is an EGFR inhibitor with IC50 of 2 nM, >1000-fold more sensitive for EGFR than human c-Src or v-Abl. Erlotinib induces autophagy.
Bemcentinib (R428) ^New

Bemcentinib (R428, BGB324) is an inhibitor of Axl with IC50 of 14 nM, >100-fold selective for Axl versus Abl. Selectivty for Axl is also greater than Mer and Tyro3 (50-to-100- fold more selective) and InsR, EGFR, HER2, and PDGFRβ (100- fold more selective).
Crizotinib (PF-02341066)

Crizotinib (PF-02341066) is a potent inhibitor of c-Met and ALK with IC50 of 11 nM and 24 nM in cell-based assays, respectively. It is also a potent ROS1 inhibitor with Ki value less than 0.025 nM. Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines.
Foretinib (GSK1363089)

Foretinib (GSK1363089, EXEL-2880, XL-880, GSK089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met (c-Met) and KDR with IC50 of 0.4 nM and 0.9 nM in cell-free assays. Less potent against Ron, Flt-1/3/4, Kit (c-Kit), PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.
Capmatinib (INCB28060)

Capmatinib (INCB28060, INC280, NVP-INC280) is a novel, ATP-competitive inhibitor of c-MET with IC50 of 0.13 nM in a cell-free assay, inactive against RONβ, as well as EGFR and HER-3. Capmatinib (INCB28060) inhibits Wnt/β-catenin and EMT signaling pathways and induces apoptosis in diffuse gastric cancer positive for c-MET amplification. Phase 1.

Features:Inactive against RONβ, another member of the c-MET RTK family, as well as EGFR and HER-3 (members of the EGFR RTK family).
Tivantinib (ARQ 197)

Tivantinib (ARQ 197) is the first non-ATP-competitive c-Met inhibitor with K_i of 0.355 μM in a cell-free assay, little activity to Ron, and no inhibition to EGFR, InsR, PDGFRα or FGFR1/4. Tivantinib (ARQ 197) induces a G2/M arrest and apoptosis. Phase 3.

Features:The first selective c-Met inhibitor to be advanced into human clinical trials.
PHA-665752

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.
BMS-777607

BMS-777607 (BMS 817378) is a Met-related inhibitor for c-Met, Axl, Ron and Tyro3 with IC50 of 3.9 nM, 1.1 nM, 1.8 nM and 4.3 nM in cell-free assays, 40-fold more selective for Met-related targets versus Lck, VEGFR-2, and TrkA/B, and more than 500-fold greater selectivity versus all other receptor and non receptor kinases. Phase 1/2.

Features:A potent inhibitor of the Met family, and >40-fold selectivity vs. Lck, VEGFR2, and TrkA/B and >500-fold selective vs. other receptor and non-receptor kinases.
SU11274

SU11274 (PKI-SU11274) is a selective Met (c-Met) inhibitor with IC50 of 10 nM in cell-free assays, no effects on PGDFRβ, EGFR or Tie2. SU11274 induces autophagy, apoptosis and cell cycle arrest.

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PF-04217903