<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Synthesis of a library of small molecule \r\ninhibitors preventing the physical interaction \r\nbetween Tec Kinase and Fibroblast Growth \r\nFactor 2, a tumor cell survival factor"^^ . "The overexpression of Fibroblast Growth Factor 2 (FGF2) is a well-known phenotype \r\nin a number of different cancer types. It acts as a very potent pro-angiogenic mitogen \r\npromoting tumour angiogenesis as well as plays a major role in tumour cell survival \r\npromoting chemo-resistance. An usual feature of FGF2 is the pathway by which it is \r\nexported from cells. Instead of being secreted through the classical ER/Golgi-dependent pathway, FGF2 is transported into the extracellular space by direct \r\ntranslocation across the plasma membrane. The underlying mechanism is based on \r\nthe formation of lipidic membrane pores, a pathway that has been classified as type I \r\nunconventional protein secretion (UPS Type I). While a number of therapeutics have \r\nbeen developed targeting FGF2 signaling in cancer cells, the elucidation of the \r\nmolecular mechanism of FGF2 secretion in the last two decades opened up unique \r\nopportunities to block the biological function of FGF2 under pathophysiological \r\nconditions.\r\nA number of cis- and trans-acting factors driving FGF2 secretion have been identified \r\nwith (i) the Na/K-ATPase that recruits FGF2 at the inner plasma membrane leaflet, (ii)\r\nTec Kinase that directly binds and phosphorylates FGF2, (iii) the membrane lipid \r\nphosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] that triggers FGF2 oligomerization \r\nand pore formation and (iv) cell surface heparan sulfate proteoglycans that capture \r\nand disassemble FGF2 oligomers at the outer plasma membrane leaflet as the final \r\nstep of this secretory process. \r\nWhile the specific role of Tec Kinase remains to be established, it has been \r\ndemonstrated that RNAi-mediated down-regulation of Tec Kinase inhibits \r\nunconventional secretion of FGF2. Recently, small molecule inhibitors have been \r\nidentified that block both physical interactions between FGF2 and Tec Kinase and \r\nFGF2 secretion from cells. They are of special interest for treating cancer types that \r\ndevelop FGF2-dependent chemo-resistance towards otherwise effective drugs such as \r\nFLT3 inhibitors in acute myeloid leukemia (AML).\r\nThe goal of this thesis was to improve the potency of FGF2/Tec inhibitors using a \r\nmedicinal chemistry approach. Starting from the most potent compound, more than \r\n130 analogues were synthesized. All compounds were tested in FGF2/Tec protein-protein interaction assays to determine their inhibitory potential. In total, thirteen \r\ncompounds were identified with improved IC50 values compared to the original \r\nFGF2/Tec inhibitor. These compounds were further evaluated in cell-based assays \r\ndetermining their influence on FGF2 secretion. Amongst this set of compounds, two \r\ncompounds were identified exerting a stronger secretion phenotype compared to the \r\noriginal FGF2/Tec inhibitor. Furthermore, through the structural design of the newly \r\nsynthesized compounds, valuable insight was obtained into the structure-activity \r\nrelationship (SAR) of the small molecule inhibitors described here. This information will \r\nbe of high value in future studies aiming at the optimization of this class of FGF2/Tec \r\ninhibitors with the final goal of developing a potent drug candidate blocking the \r\nbiological function of FGF2 under pathophysiological conditions."^^ . "2023" . . . . . . . "Alina Isabella"^^ . "Muschko"^^ . "Alina Isabella Muschko"^^ . . . . . . "Synthesis of a library of small molecule \r\ninhibitors preventing the physical interaction \r\nbetween Tec Kinase and Fibroblast Growth \r\nFactor 2, a tumor cell survival factor (PDF)"^^ . . . "2021-03-24 Alina Muschko PhD Thesis.pdf"^^ . . . "Synthesis of a library of small molecule \r\ninhibitors preventing the physical interaction \r\nbetween Tec Kinase and Fibroblast Growth \r\nFactor 2, a tumor cell survival factor (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Synthesis of a library of small molecule \r\ninhibitors preventing the physical interaction \r\nbetween Tec Kinase and Fibroblast Growth \r\nFactor 2, a tumor cell survival factor (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Synthesis of a library of small molecule \r\ninhibitors preventing the physical interaction \r\nbetween Tec Kinase and Fibroblast Growth \r\nFactor 2, a tumor cell survival factor (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Synthesis of a library of small molecule \r\ninhibitors preventing the physical interaction \r\nbetween Tec Kinase and Fibroblast Growth \r\nFactor 2, a tumor cell survival factor (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Synthesis of a library of small molecule \r\ninhibitors preventing the physical interaction \r\nbetween Tec Kinase and Fibroblast Growth \r\nFactor 2, a tumor cell survival factor (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #30409 \n\nSynthesis of a library of small molecule \ninhibitors preventing the physical interaction \nbetween Tec Kinase and Fibroblast Growth \nFactor 2, a tumor cell survival factor\n\n" . "text/html" . . . "540 Chemie"@de . "540 Chemistry and allied sciences"@en . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .