2012年考研初试应考必读实用宝典.docVIP

Title：Synthesize of N-[2-[[4-(Diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N-(1,1-dimethylethyl)urea Introduction: Most FGF receptors contain a tyrosine kinase motif downstream from the ligand binding domain and membrane spanning region. Since FGF is implicated in a variety of growth disorders and cancers, it seems reasonable that blocking the FGF signal activity via inhibition of the tyrosine activity would be of therapeutic value. So, there is currently a search for good inhibitors of this system. Stemolecule PD173074 is a potent, cell-permeable and ATP-competitive inhibitor of fibroblast growth factor (FGF) receptor1. Inhibition of the FGF signaling pathway leads to self-renewal of stem cells in many systems. Treatment of FGF2-expressing human multipotent adipose-derived stem cells with PD173074 significantly decreased their clonogenicity and differentiation potential2. Also, differentiation of mouse embryonic stem (ES) cells requires auto-inductive stimulation of the mitogen-activated protein kinase pathway by FGF43,4 including autocrine FGF45. Lung cancer is the commonest cancer killer. Small cell lung cancer (SCLC) is initially chemosensitive, but rapidly relapses in a chemoresistant form with an overall survival of 5%. Consequently, novel therapies are urgently required and will likely arise from an improved understanding of the disease biology. Our previous work showed that fibroblast growth factor-2 induces proliferation and chemoresistance in SCLC cells. Here, we show that the selective fibroblast growth factor receptor (FGFR) inhibitor PD173074 blocks H-510 and H-69 SCLC proliferation and clonogenic growth in a dose-dependent fashion and prevents FGF-2–induced chemoresistance. These effects correlate with the inhibition of both FGFR1 and FGFR2 transphosphorylation. We then determined the efficacy of daily oral administration of PD173074 for 28 days in two human SCLC models. In the H-510 xenograft, tumor growth was impaired