Better Known as: Sutent
- Marketed By: Pfizer
- Major Indication: Renal Cell Carcinoma & Gastrointestinal Cancer
- Drug Class: Receptor Tyrosine Kinase (Including VEGFR & PDGFR) & KIT Cytokine Receptor Inhibitor
- Date of FDA Approval (Patent Expiration): 2006 (2020)
- 2009 Sales: $964 Million [1]
- Importance: Currently among the most effective cancer treatments available. Sunitinib is the first treatment for renal cell carcinoma to demonstrate an overall survival of longer than two years. Has very impressive results with gastrointestinal stromal tumors. It was the first cancer drug to be approved simultaneously for two different indications. Controversial due to its high cost of $38,000 per year.
- See Pharmaceutical Drugs for more information about other drugs and disorders.
Mechanism of Action
Sunitinib 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. 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 tumors.[2] 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, , is in the "out" position, with Phe 811 occupying the ATP binding site, preventing phosphorylation and signaling. by preferentially binding and stabilizing the autoinhibited inactive conformation of KIT (IC50 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.[3]
