Dr Morgan GaddNorth West Cancer Research (NWCR) Fellow
My research is focused on the structure and function of protein-protein interactions (PPIs) and protein complexes. In particular I am interested in how they are formed and regulated within the cell, as well as how they can be selectively modulated by genetic and small molecule approaches. We use an interdisciplinary approach, combining techniques from synthetic chemistry to cell biology (and everything in between), in order to answer fundamental biological questions involving PPIs and develop new tools and therapies to target them.
Recent advances have led to the development of a new class of drug-like molecules known as proteolysis-targeting chimaeras (PROTACs), which bring a target protein and a ubiquitin E3 ligase in close proximity to facilitate ubiquitination and degradation of the target by the ubiquitin-proteasome system. These bifunctional, small molecule degraders allow any target protein of interest to be disrupted, regardless of the native target preference of the E3 ligase.
PROTACs have a number of advantages over traditional inhibitors, including:
- Low dosage requirements due to their catalytic mode of action
- The actual removal of the target from the cell
- The need only for target recognition, rather than an impact on function (i.e. inhibition)
- Enhanced target selectivity via their mode of action (cooperativity of ternary complex formation, lysine sidechain availability, etc.)
The work in my laboratory is currently focused around three general areas of developing small molecule degraders:
The discovery of selective degraders for oncoproteins – Many of the oncogenic proteins that drive cancer are either inappropriately expressed or have activating mutations within cancer cells. Thus the ability to remove these proteins from the cell is of great therapeutic interest. We are interested in making PROTACs to degrade novel targets responsible for driving cancer growth and survival for use as new chemical probes and potential therapies. In particular we aim to develop highly selective degraders by harnessing the possibilities of this technology.
Selective degradation of oncogenic mutant proteins – Most oncogenic mutations in proteins are “negative” in nature, knocking out the function of the protein or its downstream pathways. However, a small number are activating mutations, such as in the Ras proteins, which are permanently switched on by such mutations that drive cancer growth. Both structure-based ligand design and ternary complex formation provide opportunities to engineer selective targeting of mutants, both of which are encapsulated by the PROTAC approach. Such a system would allow the selective removal of mutated proteins from cancer cells, while leaving the unmutated, healthy versions of those proteins intact in healthy cells.
Elucidating a rational basis for PROTAC design – As a brand new technology there are few concepts or rules for the rational design of bifunctional degraders beyond making links in sensible places and trying as many feasible combinations as possible. We wish to establish the rules and strategies that will enable the rational design of PROTACs from existing structural and physical data for generating target potency and selectivity.
- 2017–Now: North West Cancer Research (NWCR) Fellow, Lancaster University
- 2013–2016: Postdoctoral Research Assistant, University of Dundee
- 2013: PhD (Biochemistry), University of Sydney
- 2007: BSc (Hons) Biochemistry & Chemistry, University of Sydney
Protein-protein interactions; protein-ligand interactions; protein complexes; structural biology; biophysics; x-ray crystallography; chemical biology; protein degradation; ubiquitin ligases; transcription factors; ternary complex formation; bifunctional molecules.
I teach on the following modules:
BIOL115 - Protein Biochemistry
BIOL473 - Advanced Topics in Biochemistry
PhD Supervision Interests
I am happy to supervise PhD and MSc projects on the structure and function of protein-protein interactions or protein complexes, as well as bifunctional ligands inducing PPIs, ternary complexes, and induced protein degradation.