Sunitinib (malate)

Sunitinib is a small molecule inhibitor of receptor tyrosine kinases, including FLK1 (K_i = 9 nM), PDGFRβ (K_i = 8 nM), and FLT3.^1,2 It is at least 10-fold selective for FLK1 and PDGFRβ over a variety of tyrosine kinases in a panel, including EGFR, Cdk2, Met, IGFR-1, Abl, and Src.² Sunitinib inhibits VEGF-dependent FLK1 and PDGF-dependent PDGFRβ phosphorylation (IC₅₀s = 10 and 10 nM, respectively) as well as phosphorylation of FLT3 and FLT3 carrying the activating internal tandem duplication mutation (FLT3-ITD; IC₅₀s = 250 and 50 nM, respectively).^1,2 It decreases VEGF- and FGF-induced proliferation of human umbilical vein endothelial cells (HUVECs; IC₅₀s = 30 and 700 nM, respectively) and reduces tumor growth in a variety of mouse xenograft models when administered at doses ranging from 20 to 80 mg/kg per day.² Formulations containing sunitinib have been used in the treatment of gastrointestinal stromal tumors and metastatic renal cell carcinoma.

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1. O'Farrell, A.M., Abrams, T.J., Yuen, H.A., et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101(9), 3597-3605 (2003).

2. Mendel, D.B., Laird, A.D., Xin, X., et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 9(1), 327-337 (2003).