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Design and synthesis of chemical probes for the plekstrin homology domain
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dc.contributor.advisor | Conway, Stuart | |
dc.contributor.author | Elliott, Thomas S. | |
dc.coverage.spatial | 323 | en_US |
dc.date.accessioned | 2011-08-15T11:08:03Z | |
dc.date.available | 2011-08-15T11:08:03Z | |
dc.date.issued | 2010-11-30 | |
dc.identifier | uk.bl.ethos.552493 | |
dc.identifier.uri | https://hdl.handle.net/10023/1977 | |
dc.description.abstract | The phosphatidylinositol polyphosphates play a fundamental role in intracellular signalling. Of particular importance is phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P₃], which acts by recruiting effector proteins to the cell membrane. PtdIns(3,4,5)P₃ interacts with its protein targets through selective binding domains that include the pleckstrin homology (PH) domain. The PH-domain-containing kinase, protein kinase B (PKB/Akt), which interacts with PtdIns(3,4,5)P₃, is upregulated in ~15 human malignancies. Significantly, inhibition of the PtdIns(3,4,5)P₃-PKB interaction has proved viable as a point of therapeutic intervention.There is currently a lack of small molecule probes that selectively interact with a given PH domain. Consequently, it is impossible to dissect the cellular function of PH-domain-containing proteins at a molecular level. To address this problem, we have designed and synthesised a number of derivatives of the PtdIns(3,4,5)P₃ inositol head-group – Ins(1,3,4,5)P₄. Replacement of the 5-position phosphate with a range of phosphate bioisosteres afforded compounds that displayed no binding affinity for the PH-domain of general receptor for phosphoinositides 1 (GRP1). However, it was shown that the 5-position sulfamate analogue displayed selectivity for the PH-domain of PKB. The methylphosphate biosiostere at the 1-position displayed binding for both the GRP1 PH-domain as well as the PKB PH-domain. These results demonstrate that subtle modification of the Ins(1,3,4,5)P₄ structure allows the synthesis of compounds that interact selectively with a given PH domain. We will now use these results for the synthesis of a second generation of compounds with improved PH-domain affinity and selectivity. | en_US |
dc.language.iso | en | en_US |
dc.publisher | University of St Andrews | |
dc.rights | Creative Commons Attribution 3.0 Unported | |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/ | |
dc.subject | Inositol | en_US |
dc.subject | Inositol phosphates | en_US |
dc.subject | Phosphatidylinositol | en_US |
dc.subject | Protein kinase B | en_US |
dc.subject.lcc | QP752.P52E6 | |
dc.subject.lcsh | Phosphoinositides--Derivatives--Synthesis | en_US |
dc.subject.lcsh | Inositol | en_US |
dc.subject.lcsh | Inositol phosphates | en_US |
dc.subject.lcsh | Protein kinases | en_US |
dc.subject.lcsh | Molecular probes | en_US |
dc.title | Design and synthesis of chemical probes for the plekstrin homology domain | en_US |
dc.type | Thesis | en_US |
dc.contributor.sponsor | Cancer Research UK | en_US |
dc.type.qualificationlevel | Doctoral | en_US |
dc.type.qualificationname | PhD Doctor of Philosophy | en_US |
dc.publisher.institution | The University of St Andrews | en_US |
dc.publisher.department | University of Oxford | en_US |
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