High-throughput discovery of lysine-directed probes for protein kinases

The resurgence of covalent drug discovery has yielded FDA-approved drugs in therapeutic areas as diverse as cancer, virology and sickle cell anaemia. Irreversible inhibitors usually target a nucleophilic cysteine, a strategy whose success relies on the presence of a suitable residue that is not susceptible to mutation. In the case of the protein kinases, the conserved lysine residue that is intimately involved in phosphotransfer provides a major and undertapped opportunity for the discovery of new drugs and chemical probes. <br /> <br /> In this project, we will harness a high-throughput approach to discover covalent probes that target the conserved lysine in protein kinases. The student will develop plate-based chemistry in which pairs of building blocks will be combined to yield diverse probe sets. The probe sets will be exploited to discover novel covalent modifiers of specific protein kinases. The student will harness a chemical proteomic approach to profile the proteome-wide reactivity of the discovered probes; and exploit biochemical and structural biology approaches to characterise their mechanism of action. <br /> <br /> The studentship will take advantage of the outstanding research environment of the Astbury Centre for Structural Molecular Biology, including cutting-edge structural biology and chemical proteomics capabilities.

<p>The specific objectives of the project will be:</p> <ol type="1"> <li>To develop high-throughput chemistry to enable the synthesis of diverse lysine-directed kinase probes</li> <li>To harness high-throughput experimentation to discover novel covalent modifiers of specific protein kinases</li> <li>To characterise the mechanism of discovered probes using chemical proteomic, biochemical and structural biology approaches.</li> </ol>

<p>Formal applications for research degree study should be made online through the <a href="https://www.leeds.ac.uk/research-applying/doc/applying-research-degrees">University's website</a>. Please state clearly in the Planned Course of Study section that you are applying for <em><strong>PHD Chemistry</strong></em> and in the research information section that the research degree you wish to be considered for is <em><strong>High-throughput discovery of lysine-directed probes for protein kinases</strong></em> as well as <a href="https://eps.leeds.ac.uk/chemistry/staff/4180/professor-adam-nelson">Professor Adam Nelson</a> as your proposed supervisor.  <em><strong>Please state clearly in the Finance section that the funding source you are applying for is the School of Chemistry Scholarship 2025/26 (EPSRC Research Grant APP5370).</strong></em></p> <p>If English is not your first language, you must provide evidence that you meet the University's minimum English language requirements (below).</p> <p><em>As an international research-intensive university, we welcome students from all walks of life and from across the world. We foster an inclusive environment where all can flourish and prosper, and we are proud of our strong commitment to student education. Across all Faculties we are dedicated to diversifying our community and we welcome the unique contributions that individuals can bring, and particularly encourage applications from, but not limited to Black, Asian, people who belong to a minority ethnic community, people who identify as LGBT+ and people with disabilities. Applicants will always be selected based on merit and ability.</em></p> <p style="margin-bottom:11px">Applications will be considered on an ongoing basis.  Potential applicants are strongly encouraged to contact the supervisors for an informal discussion before making a formal application.  We also advise that you apply at the earliest opportunity as the application and selection process may close early, should we receive a sufficient number of applications or that a suitable candidate is appointed.</p> <p>If you are applying with external sponsorship or you are funding your own study, please ensure you submit your application with your supporting documents by the closing date of 10 January 2025: </p> <ul> <li>Full Transcripts of all degree study or if in final year of study, full transcripts to date</li> <li>Personal Statement outlining your interest in the project</li> <li>CV</li> </ul>

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.

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. Some schools and faculties have a higher requirement.

<p class="MsoNoSpacing">A highly competitive School of Chemistry Studentship, in support of the EPSRC Research Grant APP5370: A general chemical approach to lysine-directed probes for protein kinases, providing the award of full academic fees, together with a tax-free maintenance grant at the standard UKRI rate (£19,237 in academic session 2024/25) for 3.5 years. There are no additional allowances for travel, research expenses, conference attendance or any other costs.</p> <p>You will be responsible for paying the overtime fee in full in your writing up/overtime year (£320 in Session 2024/25), but the scholarship maintenance allowance will continue to be paid for up to 6 months in the final year of award.</p> <p>Please refer to the <a href="https://www.ukcisa.org.uk/">UKCISA</a> website for information regarding Fee Status for Non-UK Nationals.</p>

<p>For further information about this project, please contact Professor Adam Nelson by email to <a href="mailto:A.S.Nelson@leeds.ac.uk">A.S.Nelson@leeds.ac.uk</a></p> <p>For further information about your application, please contact PGR Admissions by email to <a href="mailto:maps.pgr.admissions@leeds.ac.uk">maps.pgr.admissions@leeds.ac.uk</a></p>