Sorafenib: Difference between revisions

Sorafenib inhibits cellular signaling by targeting several different receptor tyrosine kinases (RTKs) including receptors for platelet-derived growth factor (PDGFRs) and [[VEGFR|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 [[cancer|tumors]].<ref>PMID: 12072198</ref> 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___, locking the inhibitor in place and stabilizing the receptor in the inactive state.<ref>PMID:18852116</ref>