Sunitinib Malate

Description

Sunitinib is a small molecule inhibitor of receptor tyrosine kinases, including FLK1 (K_i = 9 nM), PDGFRβ (K_i = 8 nM), and FLT3. 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. 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). 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. Formulations containing sunitinib have been used in the treatment of gastrointestinal stromal tumors and metastatic renal cell carcinoma.

Chemical properties

Yellow Solid

The Uses of Sunitinib Malate

Sunitinib Malate (Sutent, SU11248) is a multi-targeted RTK inhibitor targeting VEGFR2 (Flk-1) and PDGFRβ with IC50 of 80 nM and 2 nM, and also inhibits c-Kit.

The Uses of Sunitinib Malate

A multi-kinase inhibitor targeting several receptor tyrosine kinases (RTK). Antineoplastic.

The Uses of Sunitinib Malate

Sunitinib Malate is a multi-targeted RTK inhibitor targeting VEGFR2 (Flk-1) and PDGFRβ with IC50 of 80 nM and 2 nM, and also inhibits c-Kit

What are the applications of Application

Sunitinib Malate is an antineoplastic agent, Flk-1 inhibitor, and ATP-competitve inhibitor of PDGFRβ

brand name

(Pfizer).

General Description

Sunitinib is available in 12.5-, 25-, and 50-mg capsules fororal administration for the treatment of advanced RCC andGIST upon the failure of imatinib. The agent is a multikinaseinhibitor and has been shown to inhibit PDGF-R,VEGF-R, Kit, RET, and the colony-stimulating factor receptor(CSR-1R). The result of this spectrum of activity isa slowing of tumor progression and inhibition of angiogenesisboth of which are useful in the highly vascularizedcancers, RCC and GIST. The median TTP (time to tumorprogression) was 27.3 weeks for sunitinib and 6.4 weeks with a median time of 24.1 weeks for sunitinib and 6 weeksfor placebo. The agent is well absorbed upon oral administration,and both the parent and major metabolite are highly(90%–95%) protein bound. Metabolism is mediated primarilyby CYP3A4 to give the N-desethyl derivative, which isthe major metabolite (23%–37%), equally active with theparent and undergoes further metabolism by CYP3A4. Theterminal elimination half-life for the parent and N-desethylderivative are 40 to 60 hours and 80 to 110 hours, respectively.Elimination occurs primarily via the feces. Commonadverse effects of sunitinib include fatigue, diarrhea, yellowskin discoloration, anorexia, nausea, and mucositis.Mild myelosuppression has been reported in patients withGIST including neutropenia, lymphopenia, thrombocytopenia,and anemia. There have been reports of cardiotoxicityincluding decreases in left ventricular ejectionfraction, which occurred in 11% of patients during a GISTstudy.

Biological Activity

Potent, ATP-competitive VEGFR, PDGFR β and KIT inhibitor (K i values are 2, 9, 17, 8 and 4 nM for VEGFR -1, -2, -3, PDGFR β and KIT respectively). Also inhibits cellular receptor phosphorylation of FLT3, RET and CSF-1R. Exhibits antiangiogenic and antitumor activity in multiple xenograft models.

Biochem/physiol Actions

Sunitinib has greater bioavailability and potency compared to other inhibitors. It prevents angiogenesis.

storage

Store at +4°C

References

1) Deeks et al. (2006), Sunitinib; Drugs, 66 2255 2) Guo et al. (2006), Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors; Mol. Cancer. Ther., 5 1007 3) O’Farrell et al. (2003), SU11248 is a novel FLT3 yrosine kinase with potent activity in vitro and in vivo; Blood, 101 3597 4) Roskoski et al. (2007), Sunitinib: a EGF and PDGF receptor protein kinase and angiogenesis inhibitor; Biochem. Biophys. Res. Commun., 356 323