Sunitinib

Sunitinib (SU 11248) is a multi-targeted receptor tyrosine kinase inhibitor with IC₅₀s of 80 nM and 2 nM for VEGFR2 and PDGFRβ, respectively^[1]. Sunitinib, an ATP-competitive inhibitor, effectively inhibits autophosphorylation of Ire1α by inhibiting autophosphorylation and consequent RNase activation^[2]. IC50 & Target:IC50: 2 nM (PDGFRβ), 80 nM (VEGFR2)^[1] In Vitro:Sunitinib Malate is also a good inhibitor of KIT and FLT-3^[1]. In RS4;11 cells (FLT3-WT), treatment with Sunitinib (SU11248) inhibits FLT3-WT phosphorylation in a dose-dependent manner with IC₅₀ of approximately 250 nM. In MV4;11 cells that express FLT3-ITD, Sunitinib inhibits FLT3-ITD phosphorylation in a dose-dependent manner with an IC₅₀ of 50 nM following a 2-hour treatment^[3].In biochemical assays, Sunitinib (SU11248) exhibits competitive inhibition (with regard to ATP) against Flk-1 and PDGFRβ with K_i values of 9 nM and 8 nM, respectively. Sunitinib is also a competitive, albeit less potent, inhibitor of FGFR1 tyrosine kinase activity, with a K_i value of 0.83 μM. In addition to these three structurally related split kinase domain RTKs, the activity of Sunitinib has also been evaluated against a broad panel of additional tyrosine and serine/threonine kinases. In these biochemical assays, the IC₅₀ values for Sunitinib are generally at least 10-fold higher than those for Flk-1 and PDGFR (e.g., IC₅₀values of: >10 μM for EGFR and Cdk2; 4 μM for Met; 2.4 μM for IGFR-1; 0.8 μM for Abl; and 0.6 μM for Src)^[4]. In Vivo:Sunitinib Malate has very good oral bioavailability, is highly efficacious in a number of preclinical tumor models, and is well tolerated at efficacious doses^[1]. Sunitinib (80 mg/kg/day) inhibits the growth of established SF763T and Colo205 tumor xenografts in athymic mice. Sunitinib (SU11248) treatment effectively inhibits the growth of established tumor xenografts^[4].