Identification of mlm receptor antagonists for treatment of cancer

Recent high impact publications have identified antagonism of the mlm receptor as a possible target for treatment of cancer. The native ligand of the receptor has been linked to cell proliferation which has been proven to be as a result of increased nitric oxide (NO) concentration. Studies have shown that NO induces components of PKC/ERK/AP-1 signalling pathways whereby PKC stimulates activity of the mitogen activated protein kinase. This triggers a phosphorylation cascade which has been linked to the activation of genes responsible for cell differentiation and proliferation. The development of antagonists for mlm thus limiting NO concentration is therefore key to the development of cancer therapeutics. No small molecule antagonists of the mlm receptor have been reported in the literature.<br /> <br /> Our strategy will be to identify antagonists by consideration of the structures of antagonists of the closely related receptors. A database of antagonists will be generated and compounds modelled at the mlm receptor. Favoured compounds will then be synthesised and screened in the panel of mlm antagonist assays. Hits will be engineered for selectivity for the mlm receptor by comparative molecular modelling using both the mlm and structurally homologous receptors.<br /> <br />

<p>This studentship will aim to achieve the following objectives:</p> <ul> <li>to identify novel mlm antagonists as starting points for the development of novel therapeutics</li> <li>to optimise the compounds through medicinal chemistry approaches for drug-likeness and pharmaceutical and pharmacokinetic properties consistent with a bioavailable agent</li> <li>to generate selective agents (over antagonism of other receptors)</li> <li>to validate the origin of antagonism versus agonism on binding to the receptor</li> <li>to investigate high-throughput fragment screening as a tool to support the objectives of the project</li> <li>to work with our collaborators in support of the biological screening objectives of the project</li> </ul> <p> </p>

<p>To apply for this project you will need to make a formal application for research degree study through the <a href="https://www.leeds.ac.uk/research-applying/doc/applying-research-degrees">University website</a>. You will need to create a login ID with a username and PIN. </p> <p>•    For <strong>Application type</strong> please select <strong>Research Degrees – Research Postgraduate</strong>. <br /> •    The admission year for this project is <strong>2027/28</strong> Academic Year. <br /> •    You will need to select your <strong>Planned Course of Study</strong> from a drop-down menu. For this project, scroll down and select <strong>PHP Chemistry Full Time.</strong> <br /> •    The project start date for this project is <strong>1 October 2027</strong>, please use this as your <strong>Proposed Start Date of Research</strong>. <br /> •    Please state clearly in the<strong> Research Information Section</strong> that the research degree you wish to be considered for is <strong>Identification of mlm receptor antagonists for treatment of cancer</strong> as well as <a href="https://physicalsciences.leeds.ac.uk/staff/174/dr-richard-foster">Richard Foster</a> as your proposed supervisor.</p> <p><strong>Please state clearly in the Finance section</strong>, <strong>the funding that you are applying for, if you are self-funding or externally sponsored</strong>.</p> <p>More information on how to apply is available on our website <a href="https://www.leeds.ac.uk/research-applying/doc/applying-research-degrees">here</a>. You will be required to provide a personal statement which outlines your interest in the project you are applying for, why you have chosen it and how your skills map onto the requirements of the project.</p> <p>We will assess applications continuously as we receive them. We welcome and strongly encourage any potential applicants to contact the supervisor(s) for an informal discussion, prior to applying, and recommend submitting your application early.</p> <p><strong>If you are applying with external sponsorship or you are funding your own study, please ensure you provide your supporting documents at the point you submit your application:</strong></p> <ul> <li>Full Transcripts of all degree study or if in final year of study, full transcripts to date including the grading scheme</li> <li>Personal Statement outlining your interest in the project</li> <li>CV</li> </ul> <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> </p>

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>This is a non funded PhD project. Applicants are expected to be self funded or to secure external funding.</p> <p>You can find out more about our Funding Opportunities on our <a href="https://phd.leeds.ac.uk/">Postgraduate Research Opportunities</a> website.</p> <p><strong>Important: </strong>Please note that all costs associated with your arrival at Leeds (<a href="https://www.leeds.ac.uk/international-visas-immigration/doc/applying-student-visa">visa, Immigration Health Surcharge</a>, flights etc) would have to be met by yourself, or you will need to find an alternative funding source.</p>

<p>For questions related to the application process and eligibility, please contact PGR Admissions by email to <a href="mailto:epspgradmissions@leeds.ac.uk">epspgradmissions@leeds.ac.uk</a></p> <p>For further information about this project, please contact Dr Richard Foster by email to <a href="mailto:R.Foster@leeds.ac.uk">R.Foster@leeds.ac.uk</a></p>