title: Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions.
abstract: 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 the recent review by Arkin et al., which summarized the 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.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK.
authors.forename: Luca
authors.initials: L
authors.lastname: Laraia
authors.affiliation: Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK.
authors.forename: Grahame
authors.initials: G
authors.lastname: McKenzie
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Spring
authors.affiliation: Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK.
authors.forename: Ashok R
authors.initials: AR
authors.lastname: Venkitaraman
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK; Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, 19 JJ Thomson Avenue, Cambridge CB3 0HE, UK. Electronic address: djh210@cam.ac.uk.
authors.forename: David J
authors.initials: DJ
authors.lastname: Huggins
mesh_terms: D017209:Apoptosis; D001665:Binding Sites; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D060066:Protein Interaction Maps; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism
chemical_list: D011506:Proteins; D054852:Small Molecule Libraries