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Stabilizers of the interaction between 14-3-3 and hDM2 and hDMX

PGR-P-619

Key facts

Type of research degree
PhD
Application deadline
Ongoing deadline
Project start date
Thursday 1 October 2020
Country eligibility
UK and EU
Funding
Funded
Source of funding
Research council
Supervisors
Professor Andrew Wilson
Additional supervisors
Dr Thomas Edwards
<h2 class="heading hide-accessible">Summary</h2>

Transient protein-protein interactions (PPIs) control all cellular processes relevant to health and disease. Selective modulation of individual PPIs would thus facilitate both a greater understanding of biological mechanisms and provide new opportunities for therapeutic intervention. p53 is a critical tumour suppressor involved in DNA repair, inhibition of cell proliferation and cell cycle regulation. P53 is negatively regulated through interaction with hDM2 and/or hDMX. These proteins regulate localization of p53, physically block its interaction with DNA and act in concert to effect p53 degradation through ubiquitination and subsequent proteolytic degradation. In turn hDM2 and hDMX function is regulated through phosphorylation dependent interaction with the adaptor protein 14-3-3. Given that hDM2 and hDMX are overexpressed in numerous cancers, the p53/hDM2(X) interaction has received considerable attention as a drug-discovery target. This PhD project will pursue an alternative approach to target the oncogenic p53 pathway by identification and optimization of stabilizers of hDM2/14-3-3 and hDMX/14-3-3. The project will exploit our toolkit of enabling drug discovery capabilities, in house crystallographic and biophysical data on the nature of the hDM2/14-3-3 and hDMX/14-3-3 interactions together with hit matter identified from conventional screening and dynamic fragment ligation experiments. A range of methods appropriate to the target will be employed including: computational prediction, peptide chemistry, small-molecule synthesis, screening technologies, biophysics and structural-molecular biology. As a collaborative CASE studentship with AstraZeneca, a research placement in Gothenburg will form part of the studentship. This will allow the design, synthesis and testing of candidate PPI stabilizers to discover a selective and cell-permeable modulators.

<h2 class="heading hide-accessible">Full description</h2>

<p><strong><em>References</em></strong></p> <p style="margin-left:14.2pt;">1.&nbsp;&nbsp; Hoe, K. K.; Verma, C. S.; Lane, D. P., Drugging the p53 pathway: understanding the route to clinical efficacy. <em>Nat Rev Drug Discov </em><strong>2014,</strong> <em>13</em> (3), 217-236.</p> <p style="margin-left:14.2pt;">2.&nbsp;&nbsp; Nomura, K.; Klejnot, M.; Kowalczyk, D.; Hock, A. K.; Sibbet, G. J.; Vousden, K. H.; Huang, D. T., Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity. <em>Nat Struct Mol Biol </em><strong>2017,</strong> <em>24</em> (7), 578-587.</p> <p style="margin-left:14.2pt;">3.&nbsp;&nbsp; Wade, M.; Li, Y.-C.; Wahl, G. M., MDM2, MDMX and p53 in oncogenesis and cancer therapy. <em>Nat. Rev. Cancer </em><strong>2013,</strong> <em>13</em>, 83.</p> <p style="margin-left:14.2pt;">4.&nbsp;&nbsp; Wood, N. T.; Meek, D. W.; MacKintosh, C., 14-3-3 Binding to Pim-phosphorylated Ser166 and Ser186 of human Mdm2 &ndash; Potential interplay with the PKB/Akt pathway and p14ARF. <em>FEBS Lett. </em><strong>2009,</strong> <em>583</em> (4), 615-620.</p> <p style="margin-left:14.2pt;">5.&nbsp;&nbsp; Pereg, Y.; Lam, S.; Teunisse, A.; Biton, S.; Meulmeester, E.; Mittelman, L.; Buscemi, G.; Okamoto, K.; Taya, Y.; Shiloh, Y.; Jochemsen, A. G., Differential Roles of ATM- and Chk2-Mediated Phosphorylations of Hdmx in Response to DNA Damage. <em>Mol. Cell. Biol. </em><strong>2006,</strong> <em>26</em> (18), 6819-6831.</p> <p style="margin-left:14.2pt;">6.&nbsp;&nbsp; Zhao, Y.; Aguilar, A.; Bernard, D.; Wang, S., Small-Molecule Inhibitors of the MDM2&ndash;p53 Protein&ndash;Protein Interaction (MDM2 Inhibitors) in Clinical Trials for Cancer Treatment. <em>J. Med. Chem. </em><strong>2015,</strong> <em>58</em> (3), 1038-1052.</p> <p style="margin-left:14.2pt;">7.&nbsp;&nbsp; Ibarra, A. A.; Bartlett, G. J.; Heged&uuml;s, Z.; Dutt, S.; Hobor, F.; Horner, K. A.; Hetherington, K.; Spence, K.; Nelson, A.; Edwards, T. A.; Woolfson, D. N.; Sessions, R. B.; Wilson, A. J., Predicting and Experimentally Validating Hot-Spot Residues at Protein&ndash;Protein Interfaces. <em>ACS Chem. Biol. </em><strong>2019,</strong> <em>14</em> (10), 2252-2263.</p> <p style="margin-left:14.2pt;">8.&nbsp;&nbsp; Grison, C. M.; Burslem, G. M.; Miles, J. A.; Pilsl, L. K. A.; Yeo, D. J.; Imani, Z.; Warriner, S. L.; Webb, M. E.; Wilson, A. J., Double quick, double click reversible peptide &quot;stapling&quot;. <em>Chem. Sci. </em><strong>2017,</strong> <em>8</em>, 5166-5171.</p> <p style="margin-left:14.2pt;"><a href="https://wilson.leeds.ac.uk/wp-content/uploads/sites/126/2019/12/PhD-Research-Opportunity-on-Stabilizers-of-the-Interaction-between-14-3-3-and-hDM2-and-hDMX.pdf">PDF of Proposal</a></p> <p><em>This proposal is representative of the projects currently on offer in our group.&nbsp; For more details of active research projects, please visit our webpage at: <a href="https://wilson.leeds.ac.uk/">https://wilson.leeds.ac.uk/</a> </em></p>

<h2 class="heading">How to apply</h2>

<p>For this project,<strong><em> </em></strong>applications are welcome all year round&nbsp;and should be made online through the <a href="https://eps.leeds.ac.uk/chemistry-research-degrees/doc/apply">University&#39;s website</a>.</p> <p>Please state clearly in the research information section that the research degree you wish to be considered for is &ldquo;Stabilizers of the interaction between 14-3-3 and hDM2 and hDMX&rdquo; as well as <a href="https://eps.leeds.ac.uk/chemistry/staff/4193/professor-andy-wilson">Prof Andy Wilson</a> as your proposed supervisor.</p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p> <p><em>We welcome applications from all suitably-qualified candidates, but UK black and minority ethnic (BME) researchers are currently under-represented in our Postgraduate Research community, and we would therefore particularly encourage applications from UK BME candidates. All scholarships will be awarded on the basis of merit.</em></p>

<h2 class="heading heading--sm">Entry requirements</h2>

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree. Applicants are advised to check with the relevant School prior to making an application. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Graduate School prior to making an application.

<h2 class="heading heading--sm">English language requirements</h2>

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.0 overall with at least 5.5 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid.

<h2 class="heading">Funding on offer</h2>

<p><strong>UK/EU</strong> &ndash;&nbsp;EPSRC&nbsp;award paying Home/EU Fee rate, plus&nbsp;Maintenance at EPSRC rate of &pound;15,009 (Session 2019/20) per year for 3.5 years.</p>

<h2 class="heading">Contact details</h2>

<p>For further information please contact Doctoral College Admissions by email: <a href="mailto:maps.pgr.admissions@leeds.ac.uk">maps.pgr.admissions@leeds.ac.uk</a>, or by telephone: +44 (0)113 343 5700</p>