MRes – Developing novel PROTAC molecules targeting mutated BRAF (V600E) in melanoma disease: design, synthesis, and biological evaluation Project ID (SAS0215).

Melanoma ranks as the fifth most common cancer in the UK with over 132,000 new cases reported annually worldwide. According to the World Health Organization, this figure is predicted to rise significantly, reaching 500,000 by 2040. The incidence of melanoma in the UK is rising, primarily driven by heightened exposure to UV light from the sun and artificial sources such as sunbeds.

The mutation in the BRAF protein (V600E) plays a critical role in driving melanoma progression. Vemurafenib, a targeted therapy and BRAF inhibitor, has been approved to treat this mutation. However, patients often develop resistance within 6-7 months, posing a significant clinical challenge. To overcome resistance, a combination therapy involving BRAF and MEK inhibitors has also been approved, but this approach often leads to severe side effects, including bleeding, blood clots, and embryo-foetal toxicity.

PROTACs (Proteolysis Targeting Chimeras) are a class of bi-functional molecules that exploit the cell’s natural protein degradation system. Unlike traditional approaches that inhibit protein activity, PROTACs can induce the degradation of mutated protein via the proteasome-derived pathway. These molecules can be synthesised to directly target mutated proteins that are frequently resistant to traditional small molecule inhibitors. Thus, presenting an innovative therapeutic approach.

The aim of this MRes would be to develop novel PROTAC molecules targeting mutated BRAF protein (V600E), with a view to minimising side effects of current therapeutic approaches in melanoma treatment. Specifically, the project will involve the design, synthesis, and evaluation of a series of novel PROTAC molecules in cell-based assays, which will be used to select lead exemplar compounds for further evaluation in appropriate models.

We are seeking an enthusiastic, talented, and self-motivated individual with a background in medicinal chemistry (or closely related discipline) with a passion for biological evaluation to join our drug discovery research team within the School of Applied Sciences at Edinburgh Napier University.

This is a funded full-time MRes project spanning 12 months offering access to cross-disciplinary research laboratories and extensive training opportunities. While a strong foundation in chemistry is essential, this project will also provide hands-on training in appropriate cell-based assays to assess the biological effects of targeted PROTAC molecules.

As a member of Edinburgh Napier University’s Graduate College, you will be situated in the School of Applied Sciences. Throughout your studies, you will receive comprehensive support, including training and events hosted locally within the school and by our Research, Innovation, and Enterprise events team. Tailored training programs will aid in the development of both your research and transferable skills. In the School of Applied Sciences, you will have access to a diverse array of state-of-the-art facilities and expertise. You will become part of a vibrant and expanding community of postgraduate research students within the university, with access to our workspace and social spaces in our recently refurbished researcher community suite.

How to apply:

https://www.napier.ac.uk/research-and-innovation/doctoral-college/find-a-phd

Academic qualifications

A first degree (at least a 2.1) ideally in medicinal chemistry or relevant disciplines with a good fundamental knowledge of cellular biology.

English language requirement

IELTS score must be at least 6.5 (with not less than 6.0 in each of the four components). Other, equivalent qualifications will be accepted. Full details of the University’s policy are available online.

Essential attributes:

·        Experience of fundamental medicinal synthetic chemistry.

·        Experience in in vitro cell-based evaluation and tissue cultures.

·        Ability to work within a team environment.

·        Good written and oral communication skills

·        Strong motivation, with evidence of independent research skills relevant to the project.

·        Good time management

Desirable attributes:

Basic knowledge of synthesis of heterobifunctional molecules.

TO APPLY PLEASE CLICK ON THE ‘INSTITUTION WEBSITE’ LINK ON THE RIGHT-HAND SIDE OF THIS PAGE.

When applying, please quote the application reference SAS0215  on your form.

 APPLICATION CHECKLIST

·        Completed application form 

·        CV

·        2 academic references, using the Postgraduate Educational Reference Form (Found on the application process page)

·        A personal research statement (This should include (a) a brief description of your relevant experience and skills, (b) an indication of what you would uniquely bring to the project and (c) a statement of how this project fits with your future career aspirations)

·        Evidence of proficiency in English (if appropriate)