Linifanib (ABT-869)

Oral administration

HUAEC, HT-29, HT1080, A431, MDA-435, MDA-231, H526, DLD-1, 9L and MV4-11 cells

Linifanib is in a Phase III evaluation for hepatocellular carcinoma.

Linifanib (ABT-869) is a novel, potent ATP-competitive RTK inhibitor for KDR, CSF-1R, Flt-1, Flt-3 and PDGFRbeta with IC50 of 4 nM, 3 nM, 3 nM, 3 nM, and 66 nM respectively.

2% ethanol, 5% Tween 80, 20% PEG400, 73% saline

Linifanib shows inhibitory to Kit, PDGFRbeta and Flt4 with IC50 of 14 nM, 66 nM and 190 nM in kinases assay. Linifanib also inhibits ligand-induced KDR, PDGFRbeta, 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 GSK3betaat Ser9 in Ba/F3 FLT3 ITD cell lines. [3]

72 hours

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).

Linifanib (ABT-869) Chemical Structure

, , Dr. Zhang, of Tianjin Medical University, Linifanib (ABT-869)purchased from Selleck, T47D breast cancer cells were pretreated with indicated concentrations of ABT-869

2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO