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.
Targeted degradation of centrosome clustering proteins (with Dr Andrew Fielding, Lancaster) – (PDRA position available - https://hr-jobs.lancs.ac.uk/Vacancy.aspx?ref=A2840 - closes 27th November 2019) - Cancer cells that exhibit centrosome amplification will suffer from multipolar mitoses and thus cell death. To circumvent this problem, these cancers cluster their centrosomes into two distinct groups to produce a bipolar division. A number of proteins drive this process in cancer cells, and their selective knockdown using siRNA results in cancer-specific cell death. Our goal is to develop PROTAC degraders for a selective chemical knockdown of centrosome clustering proteins that may provide an alternative therapeutic approach for targeting this process in cancer 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:
BIOL253 - Genetics
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.
Structural basis of PROTAC cooperative recognition for selective protein degradation
Gadd, M.S., Testa, A., Lucas, X., Chan, K., Chen, W., Lamont, D.J., Zengerle, M., Ciulli, A. 05/2017 In: Nature Chemical Biology. 13, 5, p. 514-521. 8 p.
Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex
Cardote, T.A.F., Gadd, M.S., Ciulli, A. 6/06/2017 In: Structure. 25, 6, p. 901-911.e3. 11 p.
Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities.
Galdeano, C., Gadd, M.S., Soares, P., Scaffidi, S., van Molle, I., Birced, I., Hewitt, S., Dias, D.M., Ciulli, A. 23/10/2014 In: Journal of Medicinal Chemistry. 57, 20, p. 8657-8663. 7 p.
Small molecule induced degradation of centrosome clustering proteins: development of a novel, cancer-specific therapeutic approach
01/01/2020 → 31/12/2022