Protein-protein interactions as drug targets

Abstract

Over the last two decades, a number of protein-protein interactions (PPIs) have been targeted by the pharmaceutical industry. Pharma as a whole has historically considered PPIs to be undruggable or at the very least high-risk targets, and the relative lack of success in modulating PPIs with small molecules has done little to change this prevailing view. However, many compounds are now in clinical trials, and the experiences of the last 20 years have at the very least led to improved understanding of how to approach these challenging targets. This chapter discusses some of the issues that PPIs present as targets for small molecule modulation, with emphasis on the structural characteristics of PPIs in general, and also of classes of PPIs that share specific attributes. Grouping PPIs by structural class produces a clearer picture of both the characteristics of optimized small molecules, and the relative merits and drawbacks of various PPIs as drug targets. Within this framework, much of the past work in the PPI area is summarized through capsule descriptions of efforts directed against individual targets. Some contributors to individual successes and failures, and some insights gained from the many avenues of research followed within the PPI field are put forward. Themes of the importance of understanding the structural basis of mechanism of action and of structural support for drug discovery emerge, and guidelines for future study are offered. © 2012 Springer-Verlag Berlin Heidelberg.