摘要：

Receptor tyrosine kinases (RTKs) comprise a large family of cell surface receptors that control many critical cellular processes. It is now well established that various human diseases and pathologies are caused by dysfunction in RTKs or in the intracellular signaling pathways that they activate. These include many cancers, developmental abnormalities, sever bone disorders, immune diseases, arteriosclerosis and angiogenesis among others. We have used mass spectrometry and X-ray crystallography to demonstrate that tyrosine autophosphorylation of the catalytic tyrosine kinase domain of FGF-receptor-1 (FGFR1) is mediated by a sequential and precisely ordered reaction. We also demonstrate that the rate of catalysis of two FGFR substrates is enhanced by 50 to 100 fold following autophosphorylation of the first site in the activation loop while autophosphorylation of the second site in the activation loop results in 500 to 1000 fold increase in the rate of substrate phosphorylation. Sutent/SU11248 is a new drug that blocks the actions of several tyrosine kinases including c-Kit, PDGFR and VEGFR. Sutent has been approved by the FDA for the treatment of gastrointestinal stromal tumors (GIST), Gleevec resistant GIST, and for advanced kidney cancers The approval marks the first time the FDA has approved a new oncology product for two indications simultaneously.

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