Tethering in early target assessment

The high cost of drug discovery and development requires that the validity and druggability of targets are assessed as early as possible. Protein–protein interactions are clinically important but are usually high-risk targets when pursuing small-molecule approaches. Therefore, early target assessment might be particularly valuable when small-molecule modulation of a member from this difficult class is being considered as a means for therapeutic intervention. In this article, we first review the principles behind a fragment-based drug discovery approach known as Tethering. We then illustrate how this technique, which was initially developed to find small-molecule hits for validated targets, can also be used in the early assessment of a protein–protein interaction as a target for small molecules.