Sunitinib: Difference between revisions

Sunitinib 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. 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 [[cancer|tumors]].<ref>PMID: 12072198</ref> <scene name='Sunitinib/Kit/1'>The KIT protein</scene> 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 ([[Pharmacokinetics#Inhibitory_Concentration_.28IC50.29|IC₅₀]] for Sunitinib is 40nM for inactive conformation and 21,000nM for active conformation). KIT binds Sunitinib using residues _____. The D816 mutation of KIT, which is common to those individuals who are resistant to Sunitinib treatment, results in an IC₅₀ increase of more than 250 fold.<ref>PMID:19164557</ref>