Drug Target Strategies
Protein Homeostasis: new drug discovery directions
The emerging drug design strategy based on inducing target protein degradation offers the potential of drugging classes of proteins not previously thought to be druggable. Furthermore, the magnitude of effect for these agents is not limited by receptor occupancy and the duration of effects can persist beyond drug exposure. The current design of protein degraders is more commonly based on bivalent molecules, which consist of a ligand for the target protein linked to a ligand for a ubiquitin ligase (such as VHL, CRBN or XIAP). Due to their bivalent design, such drugs typically have a higher molecular weight than classic small molecule drugs and may present some non-ideal properties as drugs. An alternative monovalent degrader strategy is exemplified by the group of drugs termed SERDs (selective estrogen receptor degraders), for example fulvestrant. The molecular structures of SERDs are typically designed around a receptor ligand and a “degradation tail”, whose presence results in the degradation of the estrogen receptor. We have recently reported that this monovalent strategy can also be applied to the bromodomain and extra-terminal (BET) family, with the example of the monovalent BRD4 degrader GNE-0011. We will use examples of monovalent and bivalent degraders of BRD4 to compare these two complimentary degrader strategies.