Linifanib 是一种高效口服的VEGFR和PDGFR家族多靶点抑制剂，具有显著的抗肿瘤活性。它对无关 RTKs、可溶性酪氨酸激酶或丝氨酸/苏氨酸激酶的活性要低得多。它是特异性 miR-10b 抑制剂，阻断miR-10b的生物合成。

Linifanib (ABT-869) is a novel, potent ATP-competitive VEGFR/PDGFR inhibitor for KDR (IC50: 4 nM), CSF-1R (IC50: 3 nM), Flt-1/3 (IC50: 3/4 nM) and PDGFRβ (IC50: 66 nM). Linifanib may exhibit potent antiproliferative and apoptotic effects on tumor cells whose proliferation is dependent on mutant kinases, such as FMS-related tyrosine kinase receptor-3 (FLT3).

在肺组织中,Linifanib（0.3 mg/kg）使血管内皮生长因子受体磷酸化被完全抑制.在角膜上,每天两次 Linifanib（7.5/15 mg/kg）显著抑制重组碱性成纤维细胞生长因子-和血管内皮生长因子诱导的血管生成.在MDA-231移植瘤中,Linifanib（12.5 mg/kg,2次/天）可降低微脉管密度.Linifanib也抑制水肿反应（ED50：0.5 mg/kg）.作用于移植瘤模型,包括HT1080, H526, MX-1和DLD-1时,Linifanib抑制肿瘤生长（ED75：4.5-12 mg/kg）.作用于在HT1080纤维肉瘤模型中,Linifanib的Cmax和AUC24小时分别为0.4 μg/mL和2.7 μg·hour/mL.

ABT-869对血管内皮生长因子-刺激的人脐动脉内皮细胞增殖有抑制作用（IC50：0.2 nM）。在激酶实验中,Linifanib抑制Kit（IC50：14 nM）、PDGFRβ（IC50：66 nM）和Flt4（IC50：190 nM）。Linifanib也抑制细胞水平配体诱导的KDR（IC50：2 nM）、PDGFR-β（IC50：2 nM）、KIT（IC50：31 nM）和CSF-1R（IC50：10 nM）磷酸化,血清蛋白可影响该效力。在Ba/F3 FLT3 ITD细胞中,Linifanib（10 nM）降低Akt在Ser473位点磷酸化及GSK3β在Ser9位点磷酸化。然而,ABT-869几乎不影响不受血管内皮生长因子或血小板衍生因子诱导的肿瘤细胞,除MV4-11白血病细胞(具有组成型活性形式Flt3,IC50：4 nM)。Linifanib可与CSF-1R的ATP结合位点结合（Ki：3 nM）。

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.

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(Only for Reference)

796967-16-3

C21H18FN5O

375.407

RG3635;ABT-869;AL-39324

Ethanol:<1 mgml
DMSO:70 mg/mL (186.5 mM)
H2O:<1 mgml
Powder: -20°C for 3 years
In solvent: -80°C for 2 years