Vatalanib (PTK787) 2HCl

Catalog No.S1101 Synonyms: ZK 222584 (cpg-79787) 2HCl

Molecular Weight(MW): 419.73

Vatalanib (PTK787) 2HCl is an inhibitor of VEGFR2/KDR with IC50 of 37 nM in a cell-free assay, less potent against VEGFR1/Flt-1, 18-fold against VEGFR3/Flt-4. Phase 3.

3 Customer Reviews

Combinational treatment of kinase inhibitors induces the similar phenotype produced by PP1. All images are lateral view with dorsal to the top and anterior to the left. The combinational treatment of Dasatinib (D) or U0126 (U) with Sunitinib (SU),PTK787 (PTK), or ZM323881 (Z) resulted in the shrinkage of dorsal aorta.

Cell Res 2011 21, 1080-1087. Vatalanib (PTK787) 2HCl purchased from Selleck.

Mechanisms of VEGF-activated Ca2 entry. All data were from HUVECs. a, Mean 100 ng/mL VEGF-evoked Ca2 entry in the presence of 100 nmol/L sorafenib (n/N3/40), 10 nmol/L vatalanib (n/N=3/24), or 10 mol/L U73122 (n/N=3/24) normalized to their matched controls. b and c, eYFP-STIM1 (green) before (control) (b) and after exposure to 100 ng/mL VEGF (c). d, Summary data for 100 ng/mL VEGF-evoked transient and sustained Ca2 signals after transfection with STIM1.si or sc.si (n/N3/64). e, Example merged image of a cell labeled with anti-VEGFR2 antibody (green), anti-Orai1 antibody (red), and the nuclear counter stain, DAPI (blue).

Circ Res 2011 108, 1190-1198. Vatalanib (PTK787) 2HCl purchased from Selleck.
(Aa-Ja) A single row of BTs on the intact fin and stump after 6-14 dot with PTK787 and 4-12 dot with T. Small BTs appear in the fin regenerate after 8 dot with PTK787 and 6 dot with T (Da,Ea). A small BT cluster appears on the regenerate after 14 dot with PTK787 and 12 dot with T (Ga,Ha). (Ab-Jb) After 4 dot with T, BTs develop on the regenerate, stump and intact fin and continue to grow from 6-12 dot. (Jb) After 12 dot, the blood vessel network of T-treated females is similar to that of males. (Ac-Jc) PTK787-treated females do not possess BTs. (Aa-Ja,Ac-Jc) Neo-angiogenesis and regenerative outgrowth are inhibited in all PTK787-treated females. (Ad-Jd) System water controls regenerate normally and do not grow BTs. B.F., brightfield. Fli, fli1a:EGFP (green). KR21 (red) outlines the BTs. White vertical lines indicate the amputation plane. Scale bar: 100 um.

Development 2013 140, 4323-34. Vatalanib (PTK787) 2HCl purchased from Selleck.

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Biological Activity

Description

Vatalanib (PTK787) 2HCl is an inhibitor of VEGFR2/KDR with IC50 of 37 nM in a cell-free assay, less potent against VEGFR1/Flt-1, 18-fold against VEGFR3/Flt-4. Phase 3.

Targets

VEGFR2/KDR ^[1] (Cell-free assay)	VEGFR1/FLT1 ^[1] (Cell-free assay)	VEGFR2/Flk1 ^[1] (Cell-free assay)	PDGFRβ ^[1] (Cell-free assay)	VEGFR3/FLT4 ^[1] (Cell-free assay)	View More
37 nM	77 nM	270 nM	580 nM	660 nM	View More

In vitro

Vatalanib also inhibits Flk, c-Kit and PDGFRβ with IC50 of 270 nM, 730 nM and 580 nM, respectively. Furthermore, Vatalanib shows the anti-proliferation effect by inhibiting thymidine incorporation induced by VEGF in HUVECs with and IC50 of 7.1 nM, and dose-dependently suppresses VEGF-induced survival and migration of endothelial cells in the same dose range without cytotoxic or antiproliferative effect on cells that do not express VEGF receptors. ^[1] A recent study shows that Vatalanib significantly inhibits the growth of hepatocellular carcinoma cells and enhances the IFN/5-FU induced apoptosis by increasing proteins levels of Bax and reduced Bcl-xL and Bcl-2. ^[2]

In vivo

Vatalanib induces dose-dependent inhibition of the angiogenic response to VEGF and PDGF in both a growth factor implant model and a tumor cell-driven angiogenesis model after once-daily oral dosing (25-100 mg/kg). In the same dose range, Vatalanib also inhibits the growth and metastasesof several human carcinomas in nude mice without significant effect on circulating blood cells or bone marrow leukocytes. ^[1]

Protocol

Kinase Assay:^[1]	+ Expand VEGF Receptor Tyrosine Kinase Assays : The in vitro kinase assays are performed in 96-well plates as a filter binding assay, using the recombinant GST-fused kinase domains expressed in baculovirus and purified over glutathione-Sepharose. γ-[³³P]ATP is used as the phosphate donor, and poly-(Glu:Tyr 4:1) peptide is used as the acceptor. Recombinant GST-fusion proteins are diluted in 20 mM Tris·HCl (pH 7.5) containing 1–3 mM MnCl₂, 3–10 mM MgCl₂, 0.25 mg/mL polyethylene glycol 20000, and 1 mM DTT, according to their specific activity. Each GST-fused kinase is incubated under optimized buffer conditions [20 mM Tris-HCl buffer (pH 7.5), 1–3 mM MnCl₂, 3–10 mM MgCl₂, 3–8 μg/mL poly-(Glu:Tyr 4:1), 0.25 mg/mL polyethylene glycol 20000, 8 μM ATP, 10 μM sodium vanadate, 1 mM DTT, and 0.2 μCi[γ-₃₃P]ATP in a total volume of 30 μL in the presence or absence of a test substance for 10 minutes at ambient temperature. The reaction is stopped by adding 10 μL of 250 mM EDTA. Using a 96-well filter system, half the volume (20 μL) is transferred onto a Immobilon-polyvinylidene difluoride membrane. The membrane is then washed extensively in 0.5% H₃PO₄ and then soaked in ethanol. After drying, Microscint cocktail is added, and scintillation counting is performed. IC50s for PTK787/ZK 222584 or SU5416 in these as well as all assays described below are calculated by linear regression analysis of the percentage inhibition.
Cell Research:^[1]	+ Expand Cell lines: HUVECs Concentrations: 0-10 μM Incubation Time: 48 hours Method: As a test of the ability of PTK787/ZK 222584 to inhibit a functional response to VEGF, an endothelial cell proliferation assay, based on BrdUrd incorporation is used. Subconfluent HUVECs are seeded into 96-well plates coated with 1.5% gelatin and then incubated at 37 °C and 5% CO₂ in growth medium. After 24 hours, growth medium is replaced by basal medium containing 1.5% FCS and a constant concentration of VEGF (50 ng/mL), bFGF (0.5 ng/mL), or FCS (5%), in the presence or absence of PTK787/ZK 222584. As a control, wells without growth factor are also included. After 24 hours of incubation, BrdUrd labeling solution is added, and cells incubated an additional 24 hours before fixation, blocking, and addition of peroxidase-labeled anti-BrdUrd antibody. Bound antibody is then detected using 3,3′5,5′-tetramethylbenzidine substrate, which results in a colored reaction product that is quantified spectrophotometrically at 450 nm. (Only for Reference)
Animal Research:^[1]	+ Expand Animal Models: A431 epithelial carcinoma, Ls174T colon carcinoma, HT-29 colon carcinoma, PC-3 prostate carcinoma, DU145 prostate carcinoma, and CWR-22 prostate carcinoma cells are injected s.c. into the nude mice. Formulation: Vatalanib is dissolved in distilled water containing 5% DMSO and 1% Tween 80. Dosages: 25-100 mg/kg Administration: Administered via p.o. (Only for Reference)

References

Solubility (25°C)

In vitro	DMSO	85 mg/mL (202.51 mM)
	Water	10 mg/mL (23.82 mM)
	Ethanol	6 mg/mL (14.29 mM)

* 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 Vatalanib (PTK787) 2HCl SDF

Molecular Weight	419.73
Formula	C₂₀H₁₅ClN₄.2HCl
CAS No.	212141-51-0
Storage	3 years -20°C powder
Storage	2 years -80°C in solvent
Synonyms	ZK 222584 (cpg-79787) 2HCl

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Clinical Trial Information (data from https://clinicaltrials.gov, updated on 2018-11-15)

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT00390000	Active not recruiting	Unspecified Adult Solid Tumor Protocol Specific	Mayo Clinic\|National Cancer Institute (NCI)	January 2007	Phase 1
NCT00615160	Suspended	Melanoma	University of Schleswig-Holstein	December 2006	Phase 1\|Phase 2
NCT00385853	Completed	Glioblastoma	Massachusetts General Hospital\|Dana-Farber Cancer Institute\|Novartis	September 2006	Phase 1
NCT00348790	Completed	Brain and Central Nervous System Tumors\|Sarcoma	Northwestern University\|Novartis	May 2006	Phase 2
NCT00358163	Unknown status	Metastatic Non-hematologic Malignancies	Massachusetts General Hospital\|Novartis Pharmaceuticals\|Beth Israel Deaconess Medical Center\|Brigham and Women''s Hospital\|Dana-Farber Cancer Institute	April 2006	Phase 1
NCT00263198	Terminated	Breast Neoplasms	Washington University School of Medicine\|Novartis	March 2006	Phase 2

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VEGFR Signaling Pathway Map

VEGFR Inhibitors with Unique Features

Pan VEGFR Inhibitor

Regorafenib (BAY 73-4506) : Pan-VEGFR inhibitor, VEGFR1/VEGFR2/VEGFR3, IC50=13 nM/4.2 nM/46 nM.
Most Potent VEGFR Inhibitor

Axitinib : VEGFR1, VEGFR2, VEGFR3, IC50=0.1 nM, 0.2 nM, 0.1-0.3 nM.
FDA-approved VEGFR Inhibitor

Axitinib : Approved by FDA for Renal Cell Carcinoma.
Classic VEGFR Inhibitor

Dovitinib (TKI-258, CHIR-258) : Multitargeted RTK inhibitor, mostly for class III (FLT3/c-Kit) with IC50 of 1 nM/2 nM, also potent to class IV (FGFR1/3) and class V (VEGFR1-4) RTKs with IC50 of 8-13 nM.

Related VEGFR Products4

SU5402 ^New

SU5402 is a potent multi-targeted receptor tyrosine kinase inhibitor with IC50 of 20 nM, 30 nM, and 510 nM for VEGFR2, FGFR1, and PDGF-Rβ, respectively.
Erlotinib ^New

Erlotinib is an EGFR inhibitor with IC50 of 2 nM, >1000-fold more sensitive for EGFR than human c-Src or v-Abl.
R428 (BGB324) ^New

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).
Regorafenib (BAY 73-4506)

Regorafenib (BAY 73-4506) is a multi-target inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 with IC50 of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM and 2.5 nM in cell-free assays, respectively.
Axitinib

Axitinib is a multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ and c-Kit with IC50 of 0.1 nM, 0.2 nM, 0.1-0.3 nM, 1.6 nM and 1.7 nM in Porcine aorta endothelial cells, respectively.

Features:Superior as second-line therapy relative to sorafenib (current standard-of-care).
Cabozantinib (XL184, BMS-907351)

Cabozantinib (XL184, BMS-907351) is a potent VEGFR2 inhibitor with IC50 of 0.035 nM and also inhibits c-Met, Ret, Kit, Flt-1/3/4, Tie2, and AXL with IC50 of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM and 7 nM in cell-free assays, respectively.
Nintedanib (BIBF 1120)

Nintedanib (BIBF 1120) is a potent triple angiokinase inhibitor for VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β with IC50 of 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM and 59 nM/65 nM in cell-free assays. Phase 3.
Vandetanib (ZD6474)

Vandetanib (ZD6474) is a potent inhibitor of VEGFR2 with IC50 of 40 nM in a cell-free assay. It also inhibits VEGFR3 and EGFR with IC50 of 110 nM and 500 nM, respectively. Not sensitive to PDGFRβ, Flt1, Tie-2 and FGFR1 with IC50 of 1.1-3.6 μM. No activity against MEK, CDK2, c-Kit, erbB2, FAK, PDK1, Akt and IGF-1R with IC50 above 10 μM.
Lenvatinib (E7080)

Lenvatinib (E7080) is a multi-target inhibitor, mostly for VEGFR2(KDR)/VEGFR3(Flt-4) with IC50 of 4 nM/5.2 nM, less potent against VEGFR1/Flt-1, ~10-fold more selective for VEGFR2/3 against FGFR1, PDGFRα/β in cell-free assays. Phase 3.
Pazopanib

Pazopanib is a novel multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit and c-Fms with IC50 of 10 nM, 30 nM, 47 nM, 84 nM, 74 nM, 140 nM and 146 nM in cell-free assays, respectively.

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Vatalanib (PTK787) 2HCl