Sunitinib

spinqualitylabelsall models Sunitinib, also known as Sutent, (3g0e) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Better Known as: Sutent Marketed By: Pfizer Major Indication: Renal Cell Carcinoma & Gastrointestinal Cancer Drug Class: Receptor Tyrosine Kinase (Including VEGFR & PDGFR) & KIT Cytokine Receptor Inhibitor Date of FDA Approval (Patent Expiration): 2006 (2020) 2009 Sales: $964 Million Importance: Currently among the most effective cancer treatments available. Sunitinib is the first treatment for renal cell carcinoma to demonstrate an overall survival of longer than two years. Has very impressive results with gastrointestinal stromal tumors. It was the first cancer drug to be approved simultaneously for two different indications. Controversial due to its high cost of $38,000 per year. See Pharmaceutical Drugs for more information about other drugs and disorders. Mechanism of Action Sunitinib inhibits cellular signaling by targeting several different receptor tyrosine kinases (RTKs) including receptors for platelet-derived growth factor (PDGFRs) and vascular endothelial growth factor receptors (VEGFR). PDGFR and VEGFR play crucial roles in both tumor angiogenesis and cellular proliferation. Sunitinib binds at the ATP binding site of PDGFR & VEGFR, peventing the receptor kinase from binding ATP and phosphorylating their respective tyrosine target residues. Inhibition of PDGFR and VEGFR results in reduced tumor vascularization and cancer cell death. Sunitinib is also an inhibitor of KIT, a cytokine receptor inhibitor. Mutations of the KIT gene, often resulting in overexpression are associated with most gastrointestinal stromal tumors. The KIT protein is at equilibrium between two predominant confirmations, the active conformation and the autoinhibited inactive conformation. In its active conformation, KIT binds to stem cell factors, upon which KIT dimerizes and transmits second messenger signals ultimately resulting in cell survival and proliferation. In its inactive conformation, the "DFG Triad" of KIT, residues Asp 810, Phe 811, Gly 812, is in the "out" position, with Phe 811 occupying the ATP binding site, preventing phosphorylation and signaling. Sunitinib inhibits KIT by preferentially binding and stabilizing the autoinhibited inactive conformation of KIT (IC50 for Sunitinib is 40nM for inactive conformation and 21,000nM for active conformation). KIT binds Sunitinib using residues Lys 809, Val 603, Ala 621, Tyr 672, Cys 673, Leu 595, Cys 674, Gly 676, Leu 799, Glu 671 & Thr 670, locking the inhibitor in place and stabilizing the receptor in the inactive state. See also Mitogen-activated protein kinase kinase kinase kinase 1 and Sunitinib.

Pharmacokinetics

Tyrosine Kinase Inhibitor Cancer VEGFR & KIT Inhibitors cancer Inhibitors BCR-Abl Inhibitor Parameter Sunitinib (Sutent) Pharmaceutical Drugs (Nexavar) vascular endothelial growth factor receptors (Tarceva) tumors (Iressa) IC50 (Tykerb) Mitogen-activated protein kinase kinase kinase kinase 1 and Sunitinib (Gleevec) Nilotinib (Tasigna) Dasatinib (Sprycel) Tmax (hr) 8 8.3 2.0 5.4 4 3.7 3.0 1.0 Cmax (ng/ml) 24.6 460 69.6 130 115 2070 411 124 Bioavailability (%) Variable 29-49 99 59 Variable 98 30 20 Protein Binding (%) 95 99 93 90 99 95 98 96 T1/2 (hr) 83 29 9.4 26.9 9.6 26.6 16.0 3.3 AUC (ng/ml/hr) 1921 11040 20577 3850 1429 4760 10052 461 Dosage (mg) 50 50 150 250 100 400 200 200 Metabolism Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) For Pharmacokinetic Data References, see: References

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