Pushing the boundaries of protein degradation: The development of novel PROTAC technology for CNS penetration and inhaled delivery

This project is one of 19 four year PhD Studentships funded by Medical Research Scotland (https://www.medicalresearchscotland.org.uk) to be delivered jointly by the named University and External Partner Organisation (EPO). The Studentship will provide the first-class academic and additional training provided by the EPO needed to equip the successful candidate for a science career in an increasingly competitive market.

"Novel drug development technologies for CNS penetration and inhaled delivery" to be delivered by the University of Strathclyde [Supervisors: Professor William J Kerr and Dr David M Lindsay (both Department of Pure and Applied Chemistry, University of Strathclyde) and Charles River Discovery Research Services Ltd (https://www.criver.com/) [External Partner Organisation supervisor: Dr William Esmieu]. The studentship is fully collaborative with Charles River Research Discovery Services in Saffron Walden, Essex, UK, and it is expected that the location of the studentship research will be split approximately 50:50 between Charles River Research Discovery Services and the University laboratories. 

This 4 year studentship will explore the area of protein degradation through the application of proteolysis targeting chimeras (PROTACs) for central nervous system (CNS) and lung targeted therapies. The degradation of proteins that cause disease has emerged as a key area of scientific interest for drug discovery and is fast becoming established as a promising complementary strategy to traditional small molecule approaches to target inhibition. PROTACs are the most advanced class of targeted protein degraders, utilising the function of enzymes called E3 ubiquitin ligases (E3 ligases), which catalyse the tagging of proteins for removal from the body. PROTACs are bifunctional molecules (connected via a linker) in which one end binds to a protein of interest (POI) and the other binds to an E3 ligase, bringing them into close proximity. This, in turn, catalyses a process that results in natural degradation of the protein.

Whilst PROTAC technology has reached the clinic for the treatment of cancer, currently, there is very limited literature that exists for targeted delivery to the CNS or lung via inhalation. The aim of this PhD project will be to explore the structural and physicochemical properties of potential PROTAC molecules through synthesis and computational design, with a key focus on permeability for CNS penetration, and solubility and crystallinity for inhaled delivery. Biological, physicochemical, in vitro ADME and solid state profiling will drive iterative design-make-test cycles with the aim of delivering tool molecules against targets of interest.

In bringing together Academic and Industry supervision, complementary expertise in organic synthesis, medicinal chemistry, and computational chemistry will provide the PhD student with elevated levels of training in the areas of preparative chemistry, medicinal chemistry design, and data analyses. Overall, this research has the potential to significantly impact the applicability of PROTACs across a wider variety of diseases, delivering increased opportunity to improve patients’ lives.

ENQUIRIES:

Enquiries should be sent by email to Dr Laura C Paterson:

laura.c.paterson@strath.ac.uk

APPLICATIONS:

Applicants must have obtained, or expect to obtain, a strong MChem (or equivalent) degree. The position is well suited to candidates with significant experience in Synthetic Organic Chemistry and Medicinal Chemistry principles, preferably gained through industrial experience. Applicants should also have a strong interest in working at the interfaces of chemistry, biology and DMPK (drug metabolism and pharmacokinetics), as relevant to drug discovery.

Applications are welcome from UK nationals as well as EU nationals that hold UK settled or pre-settled status.

Applicants should send a CV; the contact details of 2 referees (including email addresses); full transcripts from your undergraduate degree and any previous postgraduate studies; and a covering letter detailing your experience and motivation for PhD studies, by email to Dr Laura C Paterson:

laura.c.paterson@strath.ac.uk

Please note, your application may be shared with the funders of this PhD Studentship, Medical Research Scotland and Charles River Research Discovery Services Ltd.

Interviews are expected to take place 2-3 weeks after the closing date for applications. In light of the current coronavirus situation, interviews may be conducted by video conference/conference call.

It is anticipated that the PhD Studentship will start 1 October 2021.