Overcoming Chemical, Biological and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions
Chemistry & Biology
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Laraia, L., McKenzie, G., Spring, D., Venkitaraman, A., & Huggins, D. (2015). Overcoming Chemical, Biological and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions. Chemistry & Biology, 22 689-703. https://doi.org/10.1016/j.chembiol.2015.04.019
Protein-protein interactions (PPIs) underlie the majority of biological processes, signaling and disease. Approaches to modulate PPIs with small molecules have therefore attracted increasing interest over the past decade. However, there are a number of challenges inherent in developing small molecule PPI inhibitors that have prevented these approaches from reaching their full potential. From target validation to small molecule screening and lead optimization, identifying therapeutically-relevant PPIs that can be successfully modulated by small molecules is not a simple task. Following from the recent review by Arkin et al., which summarized lessons learnt from prior successes, we focus in this article on the specific challenges of developing PPI inhibitors and detail the recent advances in chemistry, biology and computation that facilitate overcoming them. We conclude by providing a perspective on the field and outlining four innovations that we see as key enabling steps for successful development of small molecule inhibitors targeting PPIs.
Work in DRS’s laboratory is supported by the the European Union, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Medical Research Council and Wellcome Trust. Work in ARV’s laboratory is supported by the Medical Research Council and Wellcome Trust. Work in DJH's laboratory is supported by the Medical Research Council under grant ML/L007266/1. All calculations were performed using the Darwin Supercomputer of the University of Cambridge High Performance Computing Service (http://www.hpc.cam.ac.uk/) provided by Dell Inc. using Strategic Research Infrastructure Funding from the Higher Education Funding Council for England and were funded by the EPSRC under grants EP/F032773/1 and EP/J017639/1. GJM and ARV are affiliated with PhoreMost Ltd, Cambridge. We thank Alicia Higueruelo and John Skidmore for helpful discussions.
Wellcome Trust (090340/Z/09/Z)
European Research Council (279337)
Royal Society (WM150022)
External DOI: https://doi.org/10.1016/j.chembiol.2015.04.019
This record's URL: https://www.repository.cam.ac.uk/handle/1810/248292
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/