tcsc0115 Linifanib

Linifanib (ABT-869) is a multi-targeted inhibitor of VEGF and PDGFR receptor family with IC₅₀s of 3, 4, 66, 4 nM for KDR, Flt-1, PDGFRβ and FLT3.

IC50 & Target: IC50: 3 nM (KDR), 4 nM (Flt-1), 66 nM (PDGFRβ), 4 nM (FLT3)^[1]

In Vitro: Linifanib exhibits IC₅₀ values that range from 4 nM (KDR) to 190 nM (FLT4) for members of the VEGF and PDGF receptor families. Linifanib is also active against TIE2 and, to a lesser extent, RET, but is much less active (IC₅₀>10 μM) against other nonrelated tyrosine kinases, such as steroid receptor coactivator and epidermal growth factor receptor. Phosphorylation of KDR induced by VEGF is inhibited by Linifanib with an IC₅₀ of 4 nM in 3T3 murine fibroblasts engineered to express human KDR. A similar potency for inhibition of receptor autophosphorylation is seen with Linifanib when HUAECs are used as the target cell. Linifanib inhibits VEGF-stimulated phosphorylation of KDR completely at 10 nM and by 70% at 3 nM (IC₅₀=2 nM)^[1].

In Vivo: Linifanib is effective orally in the mechanism-based murine models of VEGF-induced uterine edema (ED₅₀=0.5 mg/kg) and corneal angiogenesis (>50% inhibition, 15 mg/kg). ABT-869 exhibits efficacy in human fibrosarcoma and breast, colon, and small cell lung carcinoma xenograft models (ED₅₀=1.5-5 mg/kg, twice daily) and is also effective (>50% inhibition) in orthotopic breast and glioma models. Reduction in tumor size and tumor regression is observed in epidermoid carcinoma and leukemia xenograft models, respectively^[1].