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  Design and synthesis of next-generation antibody drug conjugates to target homologous recombination deficient cancers


   Department of Pure and Applied Chemistry

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  Prof Glenn Burley, Dr Z Rattray  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

About the Project

Background

Antibody-drug conjugates (ADCs) offer a powerful strategy for the cell-selective delivery of therapeutics, while minimizing off-target interactions associated with the drug payload. A pertinent exemplar of this approach is the targeted delivery of inhibitors of DNA damage repair processes in tumour cells. However, a limitation associated with existing drugs selectively targeting DNA damage repair defects in cancer cells is their sub-optimal physicochemical properties and off-target cytotoxicity. Therefore, it is critical to develop more effective targeting strategies to deliver drugs to DNA-repair deficient malignancies. ADCs offer a route to address this challenge.

Project Objective

This goal of this PhD project is to develop novel ADCs targeting DNA damage repair deficient cancers and to develop a pipeline of analytical in vitro cell-based assays for the early-stage evaluation of these bioconjugates.

The student will develop synthetic routes to selectively attach cytotoxic payloads to antibodies. In parallel, the student will develop a pipeline of physical, chemical and biological analyses to triage ADCs throughout the course of this project. This will include the use of existing analytical methods such as mass spectrometry, flow field flow fractionation, and hydrophobic interaction chromatography as examples. Comparing traditional sites of conjugation (e.g. cysteine and lysine, via maleimide and active esters, respectively), with the emerging ‘click and stick’ approaches developed in the Burley group will give critical insight into how this variable affects key properties, as outlined below. PARP inhibitors will be used as representative drug entities with associated biological evaluation on DNA damage pathways assessed in DNA repair deficient and proficient cancer cell models.

Academic Environment 

This project is a joint interdisciplinary collaboration between the Burley and Rattray laboratories situated within Pure and Applied Chemistry (PAC) and the Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), and industrial supervision from Dr Elizabeth Love and Dr David Battersby (GSK). This project is ideally suited for students with a keen interest to work at the chemistry-biology interface using cutting-edge bioanalytical tools. Candidates are expected to possess at least an upper second-class degree (or equivalent) in a relevant Chemistry or Pharmaceutical Sciences backgrounds. The successful candidate will receive training on a wide range of technical skills including and not limited to solution and solid phase synthesis, analytical flow field flow fractionation modalities, in-cell NMR and particle analysis techniques all based within the University of Strathclyde.

The successful candidate will also benefit from a Postgraduate Certificate in Academic Practice from the University of Strathclyde. The student will benefit from working and interacting with the staff and students in two vibrant and multidisciplinary teams across PAC and SIPBS. The University of Strathclyde is currently ranked second for Pharmacy and Pharmacology in the UK Complete University Guide.


Biological Sciences (4) Chemistry (6)

Funding Notes

This is a studentship in collaboration with GSK. The successful applicant will be expected to spend at least 3 months working in collaboration with the Large Molecular Discovery group based at GSK’s Stevenage site. This studentship is open to UK and international students with (pre-)settled status and includes a stipend and fees for 3.5 years. Previous experience in bioconjugation is desirable. Candidates who are interested in this position are encouraged to send their CV, academic transcript and contact details of two referees to and . The studentship is available for an October 2024 start, or up to July 2025.


References

Burley Group
Chan et al. Bioconjugate Chemistry, 2023, 34, 2049.
Stevens et al. Journal of Medicinal Chemistry, 2023, 66, 15437.
Peschke et al. Angewandte Chemie International Edition, 2023, 62, e202313063.
Rattray Group
Rattray et al. JCI Insight, 2021, 6, e202313063.
Rattray et al. Biochemical and Biophysical Research Communications 2018, 496, 858.
Rattray et al. Cancer Research, 2018, 78, 2773.

Where will I study?

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