Strategies for targeting undruggable targets

Abstract

ABSTRACT Introduction Undruggable targets refer to clinically meaningful therapeutic targets that are ‘difficult to drug’ or ‘yet to be drugged’ via traditional approaches. Featuring characteristics of lacking defined ligand-binding pockets, non-catalytic protein–protein interaction functional modes and less-investigated 3D structures, these undruggable targets have been targeted with novel therapeutic entities developed with the progress of unconventional drug discovery approaches, such as targeted degradation molecules and display technologies. Area covered This review first presents the concept of ‘undruggable’ exemplified by RAS and other targets. Next, detailed strategies are illustrated in two aspects: innovation of therapeutic entities and development of unconventional drug discovery technologies. Finally, case studies covering typical undruggable targets (Bcl-2, p53, and RAS) are depicted to further demonstrate the feasibility of the strategies and entities above. Expert opinion Targeting the undruggable expands the scope of therapeutically reachable targets. Consequently, it represents the drug discovery frontier. Biomedical studies are capable of dissecting disease mechanisms, thus broadening the list of undruggable targets. Encouraged by the recent approval of the KRAS inhibitor Sotorasib, we believe that merging multiple discovery approaches and exploiting various novel therapeutic entities would pave the way for dealing with more ‘undruggable’ targets in the future.