Sunitinib: Difference between revisions
David Canner (talk | contribs) No edit summary |
No edit summary |
||
| (17 intermediate revisions by 3 users not shown) | |||
| Line 1: | Line 1: | ||
< | <StructureSection load='' size='350' side='right' scene='Sunitinib/Sunitinib/1' caption='Sunitinib, also known as Sutent, ([[3g0e]])'> | ||
__TOC__ | |||
===Better Known as: Sutent=== | ===Better Known as: Sutent=== | ||
* Marketed By: Pfizer<br /> | * Marketed By: Pfizer<br /> | ||
| Line 10: | Line 11: | ||
===Mechanism of Action=== | ===Mechanism of Action=== | ||
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. 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. KIT binds to stem cell | 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, <scene name='Sunitinib/Dfg/1'>residues Asp 810, Phe 811, Gly 812</scene>, is in the "out" position, with Phe 811 occupying the ATP binding site, preventing phosphorylation and signaling. <scene name='Sunitinib/Bound/2'>Sunitinib inhibits KIT</scene> by preferentially binding and stabilizing the autoinhibited inactive conformation of KIT ([[Pharmacokinetics#Inhibitory_Concentration_.28IC50.29|IC<sub>50</sub>]] 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.<ref>PMID:19164557</ref> | ||
See also [[Mitogen-activated protein kinase kinase kinase kinase 1|Mitogen-activated protein kinase kinase kinase kinase 1 and Sunitinib]]. | |||
</StructureSection> | |||
===Pharmacokinetics=== | ===Pharmacokinetics=== | ||
<table style="background: cellspacing=" | <table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%"> | ||
<tr> | <tr> | ||
<td style="width:auto; vertical-align:top;border-width: | <td style="width:auto; vertical-align:top;border-width:0px; border-style:inset"> | ||
<div style=" | <div style="height:100%; width: 100%"> | ||
{{:Tyrosine Kinase Inhibitor Pharmacokinetics}} | {{:Tyrosine Kinase Inhibitor Pharmacokinetics}} | ||
</div> | </div> | ||
| Line 26: | Line 29: | ||
<references/> | <references/> | ||
__NOEDITSECTION__ | __NOEDITSECTION__ | ||