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The Abell Group

 

We have used fragment-based approaches to target a number of protein-protein interactions. These interactions are considered challenging to target. However, we have had a success in targeting a number of these. These projects were funded through the Wellcome Trust (Seeding Drug Discovery Awards, Translation Award and Strategic Award).

PBD (Polo-box domain)

We examined the polo-box domain (PBD) of polo-like kinase (Plk1), a valid anti-cancer target whose phosphorylation-dependant protein-protein interactions are crucial for successful progression of cell mitosis. We examined this PPI using an array of biophysical techniques and identified a novel binding site. This research was in collaboration with Dr Marko Hyvönen and Professor David Spring at the University of Cambridge.

RAD51-BRCA2

We used a fragment-based approach to target the FXXA protein-protein interaction binding site on RAD51. We initially identified a number of fragments which bound to the Phe pocket and from these we were able to develop a number of small molecules inhibitors to disrupt this interaction. This research was in collaboration with Dr Marko HyvönenProfessor Tom Blundell and Professor Ashok Venkitaraman at the University of Cambridge. 

Aurora A-TPX2

We used a fragment based approach to target an allosteric site of the protein-protein interaction between Aurora A and TPX2. We identified a number of fragment hits which were elaborated to develop small molecule inhibitors to disrupt this interaction.

RAD51-FHTA protein-protein interaction:

Related Publications 

Structure-activity relationship of the peptide binding-motif mediating the BRCA2:RAD51 protein-protein interaction
DE Scott, M Marsh, TL Blundell, C Abell, M Hyvönen – FEBS letters (2016) 590, 1094
Small-molecule inhibitors that target protein-protein interactions in the RAD51 family of recombinases
DE Scott, AG Coyne, A Venkitaraman, TL Blundell, C Abell, M Hyvönen – ChemMedChem (2015) 10, 296
Using ligand-mapping simulations to design a ligand selectively targeting a cryptic surface pocket of polo-like kinase 1
YS Tan, P Śledź, S Lang, CJ Stubbs, DR Spring, C Abell, RB Best – Angew Chem Int Ed Engl (2012) 51, 10078
From crystal packing to molecular recognition: Prediction and discovery of a binding site on the surface of polo-like kinase 1
P Śledź, CJ Stubbs, S Lang, Y-Q Yang, GJ McKenzie, AR Venkitaraman, M Hyvönen, C Abell – Angew Chem Int Ed Engl (2011) 50, 4003