Targeted protein degradation for anti-cancer drug development

Abstract

Technologies to induce targeted protein degradation have been developed recently and provoke novel drug discovery research. Compounds that induce protein degradation were largely classified into two groups, molecular glues and chimeric compounds. Molecular glues such as lenalidomide interact with an E3 ubiquitin ligase CRBN and modulate the selectivity of the binding proteins to be ubiquitylated and subsequently degraded by proteasome. Another class of molecules, chimeric compounds represented by PROTACs (Proteolysis Targeting Chimeras) and SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers), are hybrids of an E3 ligand and a target ligand conjugated by an appropriate linker. Because of the modular structure of PROTACs and SNIPERs, compounds that degrade proteins of your interest can be rationally designed and chemically synthesized. Currently, more than a dozen chimeric degraders are under clinical trials.

In contrast to small molecule inhibitors, which exert their pharmacological effects by binding to their target proteins, PROTACs/SNIPERs catalytically degrade target proteins and thus exert a different pharmacological effect than small molecule inhibitors. These include more sustained suppression with lower concentration, higher selectivity to the target proteins, and suppression of all functions of the multifunctional proteins. However, when adverse effects are induced by degraders, they may be more difficult to control than inhibitors. Therefore, it is important to carefully pay attention to the potential adverse effects induced by degraders. In the symposium, I will introduce degraders with anti-cancer activity and overview future perspectives of the degraders as a novel modality for drug development.