Themed collection Modalities of induced proximity pharmacology: Degraders and Beyond themed collection

Small molecules have been shown to not only mediate and enhance polymerization, in a manner analogous to a surface residue mutation or post-translational modification, but also bind and stabilize the repeating unit to inhibit self-assembly.

In this review, we highlight bifunctional modalities that perform functions other than degradation and have great potential to revolutionize disease treatment, while also serving as important tools in basic research to explore new aspects of biology.

This review summarizes the past and present advances in developing degraders of epigenetic targets which play critical roles in many crucial biological pathways and therefore, targeted for the discovery of therapeutics.

This review summarizes the recent work of covalent chemistry in targeted protein degradation and describes the concept, pros and cons, development, and the outlook of covalent PROTACs.

ATTECs and several other emerging degrader technologies hijacking the lysosomal pathways greatly expand the spectrum of degradable targets and provide new opportunities for targeted drug discovery.

This review provides a comprehensive overview of the structure-based design of small-molecule VHL ligands and their applications as VHL inhibitors and E3 ligase recruiting moieties in PROTAC degraders.

This review provides guidelines for the optimization of proteolysis targeting chimeras (PROTACs) and outlines criteria for their use as chemical probes.

Proteolysis targeting chimeras (PROTACs) technology is a novel and promising therapeutic strategy using small molecules to induce ubiquitin-dependent degradation of proteins.

This review highlights recent approaches to characterize molecular degraders (monofunctional molecular degraders, PROTACs), or to discover their targets in vitro and in live cells, which can be extended to additional PTMs other than ubiquitination.

Targeted protein degradation is a dynamic process regulated not only by the kinetics and mechanisms of the degrader compound, but also the native homeostasis and cellular regulation of the target protein. Image created with BioRender.com.

By orchestrating interactions to an E3 ubiquitin ligase, molecular glue degraders have incredible therapeutic potential against otherwise “undruggable” proteins. We discuss how their discovery is evolving from serendipity to intentional strategies.

This review highlights important milestones in the evolution of PROTACs, briefly discusses recent lessons about targeted protein degradation, and conjectures on the efforts still needed to expand the toolbox for PROTAC discovery.

This tutorial review provides practical insights and a proposed roadmap for building the translational PK–PD understanding for protein degrader therapeutics.

This review comprehensively illustrates chemistries of E3 ligase ligands, which were used successfully in the development of PROTACs.

This tutorial review summarizes the recent progress of SERDs and their mechanism of action in the broader context of targeted protein degradation.

Thalidomide and its derivatives are the only protein degraders currently used in clinical practice. This tutorial review provides an overview of the mechanism of action of thalidomide-based degraders and their future perspectives.

In this review, we focus on recent progress towards making selective PROTAC molecules and new PROTAC technologies that will continue to push the boundaries of achieving target and tissue selectivity.

This review illustrates the design of antibody conjugates which employ chimeric protein degraders (i.e., PROTACs) as payloads and summarizes the examples of such entities that are currently known in the scientific and patent literature.