Sorafenib

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^[1]
• 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.^[2] 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.^[3] 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 , is a good model for KIT as it shares numerous structural homologies, including conformations. Sorafenib inhibits p38 in an identical manner as it does KIT, by preferentially binding and stabilizing the autoinhibited inactive conformation of p38. 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.^[4]

Pharmacokinetics