title: Synthesis of a library of small molecule   inhibitors preventing the physical interaction   between Tec Kinase and Fibroblast Growth   Factor 2, a tumor cell survival factor
creator: Muschko, Alina Isabella
subject: 540
subject: 540 Chemistry and allied sciences
subject: 570
subject: 570 Life sciences
description: The overexpression of Fibroblast Growth Factor 2 (FGF2) is a well-known phenotype   in a number of different cancer types. It acts as a very potent pro-angiogenic mitogen   promoting tumour angiogenesis as well as plays a major role in tumour cell survival   promoting chemo-resistance. An usual feature of FGF2 is the pathway by which it is   exported from cells. Instead of being secreted through the classical ER/Golgi-dependent pathway, FGF2 is transported into the extracellular space by direct   translocation across the plasma membrane. The underlying mechanism is based on   the formation of lipidic membrane pores, a pathway that has been classified as type I   unconventional protein secretion (UPS Type I). While a number of therapeutics have   been developed targeting FGF2 signaling in cancer cells, the elucidation of the   molecular mechanism of FGF2 secretion in the last two decades opened up unique   opportunities to block the biological function of FGF2 under pathophysiological   conditions.  A number of cis- and trans-acting factors driving FGF2 secretion have been identified   with (i) the Na/K-ATPase that recruits FGF2 at the inner plasma membrane leaflet, (ii)  Tec Kinase that directly binds and phosphorylates FGF2, (iii) the membrane lipid   phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] that triggers FGF2 oligomerization   and pore formation and (iv) cell surface heparan sulfate proteoglycans that capture   and disassemble FGF2 oligomers at the outer plasma membrane leaflet as the final   step of this secretory process.   While the specific role of Tec Kinase remains to be established, it has been   demonstrated that RNAi-mediated down-regulation of Tec Kinase inhibits   unconventional secretion of FGF2. Recently, small molecule inhibitors have been   identified that block both physical interactions between FGF2 and Tec Kinase and   FGF2 secretion from cells. They are of special interest for treating cancer types that   develop FGF2-dependent chemo-resistance towards otherwise effective drugs such as   FLT3 inhibitors in acute myeloid leukemia (AML).  The goal of this thesis was to improve the potency of FGF2/Tec inhibitors using a   medicinal chemistry approach. Starting from the most potent compound, more than   130 analogues were synthesized. All compounds were tested in FGF2/Tec protein-protein interaction assays to determine their inhibitory potential. In total, thirteen   compounds were identified with improved IC50 values compared to the original   FGF2/Tec inhibitor. These compounds were further evaluated in cell-based assays   determining their influence on FGF2 secretion. Amongst this set of compounds, two   compounds were identified exerting a stronger secretion phenotype compared to the   original FGF2/Tec inhibitor. Furthermore, through the structural design of the newly   synthesized compounds, valuable insight was obtained into the structure-activity   relationship (SAR) of the small molecule inhibitors described here. This information will   be of high value in future studies aiming at the optimization of this class of FGF2/Tec   inhibitors with the final goal of developing a potent drug candidate blocking the   biological function of FGF2 under pathophysiological conditions.
date: 2023
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/30409/1/2021-03-24%20Alina%20Muschko%20PhD%20Thesis.pdf
identifier: DOI:10.11588/heidok.00030409
identifier: urn:nbn:de:bsz:16-heidok-304096
identifier:   Muschko, Alina Isabella  (2023) Synthesis of a library of small molecule inhibitors preventing the physical interaction between Tec Kinase and Fibroblast Growth Factor 2, a tumor cell survival factor.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/30409/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng