Advances and opportunities in targeted protein degradation

Abstract

We are excited to welcome you to our special Review issue in Cell Chemical Biology on Advances and Opportunities in Targeted Protein Degradation. Over the past decade, targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) and molecular glue degraders has become one of the hottest areas in drug discovery because of the potential for specifically degrading and eliminating any disease-causing protein. TPD using PROTACs or molecular glues employs heterobifunctional or monovalent molecules, respectively, to induce the proximity of E3 ubiquitin ligases to target proteins of interest for ubiquitination and proteasome-mediated degradation. Exciting aspects of TPD include the potential of this approach to therapeutically target “undruggable” disease-causing proteins, which have eluded classical drug discovery efforts, given small-molecule degraders only require an E3 ligase binder to the target protein, and not necessarily a consequential inhibitor. In contrast to small-molecule inhibitors that usually function by stoichiometrically occupying the active site of target proteins, TPD enables the catalytic degradation of target proteins resulting in sub-stoichiometric degradation of target proteins. In addition, for proteins that possess both enzymatic and scaffolding functions where inhibitors for the target protein may only partially alter the protein function, TPD and degrading the whole protein can confer added therapeutic properties beyond simple inhibitors. Despite the promise of TPD in drug discovery, several challenges still exist, including the necessity to discover more chemical matter for the >600 E3 ligases and developing approaches for the rational discovery of molecular glue degraders. In this special issue, we aim to highlight a few of the key advances in the field of targeted protein degradation. The 15 review articles included within this issue highlight the achievements made in the TPD field and innovations in expanding the scope of TPD, and address remaining challenges and opportunities in this area. We begin with reviews that provide an introduction into the ubiquitin-proteasome system and the chemical tools and probes developed to study the basic biology underlying this system and how these systems become dysregulated in disease. Schulman and Henneberg discuss various chemical tools and probes that have been developed to enable the basic understanding of the ubiquitin system. Margolis and colleagues delve deep into the biology of proteosomes and their roles in protein degradation in mammalian cells to maintain protein homeostasis with a particular emphasis on specialized proteasomes in the nervous system. Pagano and Duan give a broad overview of the accumulating evidence highlighting the role of E3 ubiquitin ligases in driving cancer, acting as either tumor suppressors or tumor promoters. Next, we cover reviews that showcase TPD using heterobifunctional degraders and their successes both as chemical tools and as drugs in clinical development. Crews and Samarasinghe highlight PROTACs and their utility in tackling the undruggable proteome and the various protein classes that are important in disease that have been targeted by PROTACs. They also discuss their next-generation approaches to TPD with transcription factor targeting chimeras (TRAFTACs). Bernardes, Winter, and Kiely-Collins discuss the pros and cons of reversible covalent, irreversible covalent, and reversible covalent PROTACs in TPD. Trauner and Reynders review light-activated PROTACs and molecular glues to provide precise temporal and spatial control of protein levels. The next set of reviews delves deep into small molecules that target E3 ubiquitin ligases that have been exploited for targeted protein degradation through either molecular glues or PROTACs. We start with Handa and colleagues exploring the history of the E3 ligase cereblon (CRBN) and their discovery that the sedative thalidomide caused severe birth defects by targeting CRBN and acting as a molecular glue between CRBN and neo-substrate proteins to induce their ubiquitination and degradation. This review then subsequently describes how thalidomide derivatives were later developed into anti-cancer drugs through also exploiting CRBN-mediated molecular glue interactions with tumor-promoting targets to induce their degradation, and then covers the use of these thalidomide derivatives in PROTACs. Rape and colleagues then discuss additional E3 ligases that have been successfully exploited by small molecules for TPD and propose new ubiquitination enzymes that can potentially be harnessed for drug discovery and TPD. Dikic and Kannt further elaborate on the challenges that face the TPD field, in that only about 2% of the more than 600 E3 ligases have currently been targeted with small molecules. They provide an overview of the major classes of E3 ligases, the specific E3 ligases that have been exploited for TPD, approaches used to identify or design E3 ligase-targeting ligands, and the challenges and opportunities that exist in expanding the arsenal of small-molecule ligands against E3 ligases. The next set of reviews then delves into approaches for discovering new molecular glue degraders. Thoma and Kozicka review strategies by which E3 ligases can be reprogrammed by molecular glue degraders and describe how modifications of the protein surface by small molecules can change the protein interactome. Winter and colleagues describe approaches for discovering new E3 ligase ligands and molecular glue degraders using unbiased multi-omic strategies and discuss the pros and cons of each method. The following three reviews discuss using small molecules to influence protein stability using approaches beyond E3 ligase recruitment. Arimoto and Takahashi discuss TPD via autophagy-based degraders or autophagy targeting chimeras (AUTACs) instead of degraders that exploit the ubiquitin-proteasome system. These autophagy-based degraders have the potential to degrade much larger cellular cargo, including organelles and aggregate-prone proteins. Bertozzi and colleagues review their recent development of lysosome-targeting chimeras (LYTACs) that co-opt internalizing receptors to degrade secreted and membrane-anchored targets. Choudhary and colleagues review recent advances in induced proximity paradigms beyond degradation, including their recent development of kinase recruiters and targeted protein phosphorylation approaches as well as future approaches for targeted manipulation of protein post-translational modifications. They further describe the potential biological applications of this emerging class of molecules to complement and expand current therapeutic strategies. Finally, Buhrlage and colleagues also discuss targeting deubiquitinating enzymes (DUBs) with small-molecule inhibitors to investigate DUB function and explore DUB inhibitors for disease therapy. As described in these 15 reviews, the field of TPD has rapidly evolved, particularly in recent years, as molecular glue degraders and PROTACs either enter clinical development or make significant impact in the clinic. Over the next several years, TPD with molecular glue degraders, PROTACs, AUTACs, LYTACs, and many other emerging modalities is likely to make a major impact in drug discovery and improving disease outcomes. Looking to the future, induced proximity paradigms with molecular glues, next-generation TPD approaches, and modalities that go beyond degradation are also likely to make a major impact in drug discovery. Cell Chemical Biology will continue to bring attention to the rapidly developing area of chemical biology and highlight significant technical, biological, and translational advancements in the area of targeted protein degradation and induced proximity that are of value and interest to our broad readership.