Sorafenib

spinqualitylabelsall models Sorafenib, also known as Nexavar, (3heg) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Better Known as: Nexavar Marketed By: Bayer Healthcare & Onyx Pharmaceuticals Major Indication: Renal Cell Carcinoma & Kidney Cancer Drug Class: Receptor Tyrosine Kinase (Including VEGFR & PDGFR) & KIT Cytokine Receptor Inhibitor Date of FDA Approval (Patent Expiration): 2005 (2020) 2009 Sales: ~$904 Million Importance: Currently among the most effective Renal and Liver cancer treatments available. Part of the new tyrosine kinase inhibitor drug class. Has very impressive results with renal and liver cancer, nearly doubling progression free survival compared to the palcebo group although without impacting quality of life measurements likely due to the relatively harsh side effect profile inherent to any multi kinase inhibitor. Controversial due to its high cost of $70,000 per year. See Pharmaceutical Drugs for more information about other drugs and disorders. Mechanism of Action Sorafenib 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. Sorafenib binds 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. Sorafenib is also an inhibitor of KIT, a cytokine receptor inhibitor. Mutations of the KIT gene, often resulting in overexpression, are associated with cancerous 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. The mitogen activated protein kinase, p38, is a good model for KIT as it shares numerous structural homologies, including the DFG triad conformations. Sorafenib inhibits p38 in an identical manner as it does KIT, by preferentially binding and stabilizing the autoinhibited inactive conformation of p38. P38 binds Sorafenib using residues Glu 71, Leu 74, Val 83, Ile 166, His 148, Ile 84, Leu 167, Thr 106, His 107, Met 109, locking the inhibitor in place and stabilizing the receptor in the inactive state. Pharmacokinetics Tyrosine Kinase Inhibitor Pharmacokinetics VEGFR & KIT Inhibitors EGFR Inhibitors BCR-Abl Inhibitor Parameter Sunitinib (Sutent) Sorafenib (Nexavar) Erlotinib (Tarceva) Gefitinib (Iressa) Lapatinib (Tykerb) Imatinib (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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