How to make an undruggable enzyme druggable: lessons from ras proteins

Significant advances have been made toward discovering allosteric inhibitors for challenging drug targets such as the Ras family of membrane-associated signaling proteins. Malfunction of Ras proteins due to somatic mutations is associated with up to a quarter of all human cancers. Computational techniques have played critical roles in identifying and characterizing allosteric ligand-binding sites on these proteins, and to screen ligand libraries against those sites. These efforts, combined with a wide range of biophysical, structural, biochemical and cell biological experiments, are beginning to yield promising inhibitors to treat malignancies associated with mutated Ras proteins. In this chapter, we discuss some of these developments and how the lessons learned from Ras might be applied to similar other challenging drug targets.