Small molecule modulation of protein polymerization
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.
Chemistries of bifunctional PROTAC degraders
Proteolysis targeting chimeras (PROTACs) technology is a novel and promising therapeutic strategy using small molecules to induce ubiquitin-dependent degradation of proteins.
Methods to characterize and discover molecular degraders in cells
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.
Review Article
The importance of cellular degradation kinetics for understanding mechanisms in targeted protein degradation
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.
Chasing molecular glue degraders: screening approaches
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.
PROTACs: past, present and future
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.
Translational PK–PD for targeted protein degradation
This tutorial review provides practical insights and a proposed roadmap for building the translational PK–PD understanding for protein degrader therapeutics.
E3 ligase ligand chemistries: from building blocks to protein degraders
This review comprehensively illustrates chemistries of E3 ligase ligands, which were used successfully in the development of PROTACs.
Tutorial Review
Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders
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.
Target and tissue selectivity of PROTAC degraders
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.
Degrader-antibody conjugates
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.
About this collection
Recruiting proteins and other biological macromolecules into spatial proximity is offering a revolutionary new paradigm of chemical biology and drug discovery. Fueled by the remarkable success and clinical reality of degraders such as PROTACs and molecular glues, the approach of bringing proteins together and inducing de novo protein-protein interactions is witnessing an exponential surge in interest and attention across academia and industry. These approaches can modulate target stability, chemical composition, and ultimately function, and as such promise to expand the range of tractable biomolecules.
With this themed collection, Guest Edited by Alessio Ciulli (University of Dundee) and Shaomeng Wang (University of Michigan), we aim to cover the breadth and depth of topics in this expanding new field: from different flavours of degrader molecules, including developments in chemistry and mechanistic understanding, to novel approaches to induced proximity beyond degraders, including modern enabling technologies.