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Design and synthesis of chemical probes for the protein kinase B PH domain

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JosephNemethPhDThesis.pdf (3.811Mb)
Date
25/06/2008
Author
Nemeth, Joseph
Supervisor
Conway, Stuart J.
Funder
Engineering and Physical Sciences Research Council (EPSRC)
Prosidion Limited
Keywords
Protein kinase B
Phosphatidylinositol-3,4,5-trisphosphate
PH domain
Phosphoinositide-3-kinase
Akt
InsP4 analogue
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Abstract
Phosphatidyl D-myo-inositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] contributes to the activation of protein kinase B (PKB) by interacting with the PKB PH domain. PKB is known to be up-regulated in several cancer cell types. Compounds that can display selective inhibition of this kinase have promising chemotherapeutic potential, and inhibition of the PH domain of PKB represents a realistic means by which to achieve this. Analysis of the X-ray crystal structures of apo PKBαPH and PKBαPH bound to D-myo-inositol 1,3,4,5-tetrakisphosphate [InsP4, the inositol head group of PtdIns(3,4,5)P3] led to the design of PtdIns(3,4,5)P3 and InsP4 analogues as potential PKB PH domain inhibitors. The synthesis of PtdIns(3,4,5)P3 analogues modified at the C-4 position was investigated, but it was discovered that such compounds were prone to migration of the 1-position phosphate. Subsequently, a range of racemic InsP4 analogues, modified at the C-1 or C-4 position, were successfully synthesised. Advanced progress has also been made towards the synthesis of enantiomerically pure analogues of InsP4.
Type
Thesis, PhD Doctor of Philosophy
Collections
  • Chemistry Theses
URI
http://hdl.handle.net/10023/572

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