Home Protein Tyrosine Kinase VEGFR inhibitor - CSF-1R inhibitor - PDGFR inhibitor - FLT3 inhibitor - Autophagy activator - Apoptosis related activator Linifanib (ABT-869) For research use only.

Linifanib (ABT-869)

Synonyms: AL39324,RG3635

Linifanib (ABT-869, AL39324, RG3635) 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). Linifanib (ABT-869) induces autophagy and apoptosis. Phase 3.

Linifanib (ABT-869) Chemical Structure

Linifanib (ABT-869) Chemical Structure

CAS No. 796967-16-3

Purity & Quality Control

Linifanib (ABT-869) Related Products

Signaling Pathway

VEGFR Signaling Pathways

VEGFR Signaling Pathway

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
mouse 3T3 cells Function assay Inhibition of VEGF-induced human KDR phosphorylation in mouse 3T3 cells by ELISA, IC50=0.004 μM 17343372
Sf9 insect cells Function assay 120 mins Inhibition of recombinant GST-tagged VEGFR2 expressed in Sf9 insect cells after 120 mins by Kinase-Glo assay, IC50=5 nM 21708468
human MOLM13 cells Cytotoxicity assay 72 h Cytotoxicity against human MOLM13 cells harboring mutant FLT3 after 72 hrs by MTS assay, GI50=0.037 μM 23618709
human MV4-11 cells Proliferation assay 72 h Antiproliferation activity against FLT3/ITD harboring human MV4-11 cells after 72 hrs by MTS method, GI50=0.04 μM 21708468
human MOLT4 cells Proliferation assay 72 h Antiproliferation activity against human MOLT4 after 72 hrs by MTS method, GI50=6.7 μM 21708468
RS4:11 cells Proliferation assay 72 h Antiproliferation activity against human RS4:11 cells expressing wild type FLT3 after 72 hrs by MTS method, GI50=9.2 Μm 21708468
U937 cells Proliferation assay 72 h Antiproliferation activity against human FLT3 gene-deficient U937 cells after 72 hrs by MTS method, GI50=19 μM 21708468
Click to View More Cell Line Experimental Data

Biological Activity

Description Linifanib (ABT-869, AL39324, RG3635) 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). Linifanib (ABT-869) induces autophagy and apoptosis. Phase 3.
Targets
VEGFR1/FLT1 [1]
(Cell-free assay)		 CSF-1R [1]
(Cell-free assay)		 VEGFR2/KDR [1]
(Cell-free assay)		 FLT3 [1]
(Cell-free assay)		 Kit [1]
(Cell-free assay)		 Click to View More Targets
3 nM 3 nM 4 nM 4 nM 14 nM
In vitro
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]
Kinase Assay 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 Research 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
Experimental Result Images Methods Biomarkers Images PMID
Western blot phospho-FLT3 / FLT3 Beclin-1 / ATG5 / ATG7 / p62 p-PDGFRβ / PDGFRβ/ p-AKT / AKT / p-mTOR / mTOR / p-S6K 21471285
Immunofluorescence LC3 25327881
In Vivo
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]
Animal Research 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.
Dosages ~ 10 mg/kg
Administration Oral administration
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01401933 Completed
Advanced Solid Tumors
Abbott
 May 2011 Phase 1
NCT01381341 Completed
Advanced Solid Tumors
Abbott
 May 2011 Phase 1
NCT01114191 Completed
Solid Tumors
Abbott
 May 2010 Phase 1

Chemical Information & Solubility

Molecular Weight 375.41 Formula

C21H18FN5O
CAS No. 796967-16-3 SDF Download Linifanib (ABT-869) SDF
Smiles CC1=CC(=C(C=C1)F)NC(=O)NC2=CC=C(C=C2)C3=C4C(=CC=C3)NN=C4N
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 75 mg/mL ( (199.78 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble


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