Linifanib (ABT-869)

Linifanib (ABT-869) is a novel, potent ATP-competitive VEGFR/PDGFR inhibitor for KDR, CSF-1R, Flt-1/3 and PDGFRβ with IC50 of 4 nM, 3 nM, 3 nM/4 nM and 66 nM respectively, mostly effective in mutant kinase-dependent cancer cells (i.e. FLT3). Phase 3.

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Linifanib (ABT-869) Chemical Structure

Linifanib (ABT-869) Chemical Structure
Molecular Weight: 375.41

Validation & Quality Control

Customer Reviews(2)

Quality Control & MSDS

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Product Description

Biological Activity

Description Linifanib (ABT-869) is a novel, potent ATP-competitive VEGFR/PDGFR inhibitor for KDR, CSF-1R, Flt-1/3 and PDGFRβ with IC50 of 4 nM, 3 nM, 3 nM/4 nM and 66 nM respectively, mostly effective in mutant kinase-dependent cancer cells (i.e. FLT3). Phase 3.
Targets VEGFR1/FLT1 [1] CSF-1R [1] VEGFR2/KDR [1] FLT3 [1] Kit [1]

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IC50 3 nM 3 nM 4 nM 4 nM 14 nM
In vitro Linifanib shows inhibitory to Kit, PDGFRβ and Flt4 with IC50 of 14 nM, 66 nM and 190 nM in kinases assay. Linifanib also inhibits ligand-induced KDR, PDGFRβ, Kit, and CSF-1R phosphorylation with IC50 of 2 nM, 2 nM, 31 nM and 10 nM at cellular level and this cellular potency could be affected by serum protein. Linifanib suppresses VEGF-stimulated HUAEC proliferation with IC50 of 0.2 nM. While Linifanib has weak activity against tumor cells which are not induced by VEGF or PDGF, except for MV4-11 leukemia cells (with constitutively active form of Flt3) with IC50 of 4 nM. Linifanib could cause a decrease in S and G2-M phases with a corresponding increase in the sub-G0-G1 apoptotic population in MV4-11 cells. [1] Linifanib binds to the ATP-binding site of CSF-1R with Ki of 3 nM. [2] Linifanib (10 nM) exhibits a reduced phosphorylation of Akt at Ser473 and decreased phosphorylation of GSK3βat Ser9 in Ba/F3 FLT3 ITD cell lines. [3]
In vivo Linifanib (0.3 mg/kg) results in complete inhibition of KDR phosphorylation in lung tissue. Linifanib also inhibits the edema response with ED50 of 0.5 mg/kg. Linifanib (7.5 and 15 mg/kg, bid) significantly inhibits both bFGF- and VEGF-induced angiogenesis in the cornea. Linifanib inhibits tumor growth in flank xenograft models including HT1080, H526, MX-1 and DLD-1 with ED75 from 4.5-12 mg/kg. Linifanib also shows efficacy in A431 and MV4-11 xenografts at low dose levels. Linifanib (12.5 mg/kg bid) reveals a decrease of microvasculure density in MDA-231 xenograft. Linifanib shows a Cmax and AUC24 hours with 0.4 μg/mL and 2.7 μg•hour/mL in HT1080 fibrosarcoma model. [1]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Kinase assays Potencies (IC50 values) are determined by assays of active kinase domains cloned and expressed in baculovirus using the FastBacbaculovirus expression system or obtained commercially. For tyrosine kinase assays, a biotinylated peptide substrate containing a single tyrosine is used with 1 mM ATP, anEu-cryptate–labeled anti-phosphotyrosine antibody (PT66), and Strepavidin-APC in a homogeneous time-resolved fluorescence assay. Serine/threonine kinases are assayed using 5 μM ATP, [33P]ATP, and a biotinylated peptide substrate with peptide capture and incorporation of 33P determined using a SA-Flashplate. Linifanib is assayed at multiple concentrations prepared by serial dilution of a DMSO stock solution of Linifanib. The concentration resulting in 50% inhibition of activity is calculated using nonlinear regression analysis of the concentration response data.

Cell Assay: [1]

Cell lines HUAEC, HT-29, HT1080, A431, MDA-435, MDA-231, H526, DLD-1, 9L and MV4-11 cells
Concentrations 0-100 μM
Incubation Time 72 hours
Method Cells are seeded into 96-well plates at 2.5 × 103 per well and incubated with serum-free medium for 24 hours. Linifanib and VEGF (final, 10 ng/mL) are added and incubated for 72 hours in serum-free medium. For carcinoma cell lines, 3 × 103 cells/well are plated overnight in full growth medium. Linifanib is added to the cells in full growth medium and incubated for 72 hours. For leukemia cells, generally 5 × 104 per well are plated in full growth medium, Linifanib is added, and incubated for 72 hours. The effects on proliferation are determined by addition of Alamar Blue (final solution, 10%), incubation for 4 hours at 37 °C in a CO2 incubator and analysis in a fluorescence plate reader (544 nm, excitation: 590 nm, emission

Animal Study: [1]

Animal Models H526, DLD-1, MDA-231, MDA-435LM, HCT-116, H526, DLD-1, MDA-231, MDA-435LM, MV4-11 and MX-1 xenografts are established in mice.
Formulation 2% ethanol, 5% Tween 80, 20% PEG400, 73% saline
Dosages ~ 10 mg/kg
Administration Oral administration
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/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.

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

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
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] Albert DH, et al. Mol Cancer Ther, 2006, 5(4), 995-1006.

[2] Guo J, et al. Mol Cancer Ther, 2006, 5(4), 1007-1013.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-10-16)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01506934 Terminated Advanced or Metastatic Solid Tumors Abbott October 2011 Phase 1
NCT01286974 Terminated Advanced Solid Tumors Abbott August 2011 Phase 1
NCT01365910 Terminated Recurrent Colon Cancer|Recurrent Rectal Cancer|Stage IVA Colon Cancer|Stage IVA Rectal Cancer|Stage IVB Colon Cancer|Stage IVB Rectal Cancer Vanderbilt-Ingram Cancer Center June 2011 Phase 2
NCT01413893 Completed Advanced Solid Tumors Abbott June 2011 Phase 1
NCT01381341 Completed Advanced Solid Tumors Abbott May 2011 Phase 1

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Chemical Information

Download Linifanib (ABT-869) SDF
Molecular Weight (MW) 375.41
Formula

C21H18FN5O

CAS No. 796967-16-3
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms AL39324,RG3635
Solubility (25°C) * In vitro DMSO 75 mg/mL (199 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 30 mg/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 1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea

Research Area

Customer Reviews (2)


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Rating
Source Liver Int 2011 32, 400-409. Linifanib (ABT-869) purchased from Selleck
Method Quantification of apoptosis, TUNEL assay
Cell Lines KMCH-1 cells, LX-2 cells
Concentrations 0.5 µmol/L
Incubation Time 24 h
Results KMCH-1 cells were more resistant to TRAIL-induced apoptosis when co-cultured with LX-2 cells when compared with monoculture conditions, a cytoprotective effect that was significantly attenuated by Linifanib.

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Rating
Source Dr. Zhang of Tianjin Medical University. Linifanib (ABT-869) purchased from Selleck
Method Western blotting
Cell Lines T47D breast cancer cells
Concentrations 0-2.5 μM
Incubation Time
Results ABT-869 increased protein expression levels of Bcl-xl and Bcl2 in T47D breast cancer cells.

Product Citations (2)

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