A Structural and Biophysical Perspective of Degrader Activity Through Ternary Complex Formation

Gadd, M.S. and Aublette, M.C. (2023) A Structural and Biophysical Perspective of Degrader Activity Through Ternary Complex Formation. In: Inducing Targeted Protein Degradation : from Chemical Biology to Drug Discovery and Clinical Applications. Wiley. ISBN 9783527350131

Abstract

Targeted protein degradation (TPD) is a powerful approach in mechanistic cell biology studies and at its advanced stage shows promise in therapeutic applications, with several degrader molecules currently being in clinical trials. At its core, TPD relies on co-opting cellular pathways to enable the controlled, selective degradation of proteins of interest (POIs). Hijacking cellular degradation pathways requires their detailed molecular understanding and most importantly defining biological effectors that confer substrate selectivity and commitment to degradation. Chemical biology or therapeutic strategies that induce proximity between POIs and these biological effectors enable TPD. Conversely, using these chemical biology strategies can support work aimed at understanding cellular degradation pathways. This interrelation creates a powerful cycle in which fundamental cell biology research progresses the development of TPD strategies and vice versa. In this chapter, we provide an overview of degradation pathways in different organelles in eukaryotic cells and discuss their underlying molecular mechanisms. We review successful strategies for hijacking these pathways for TPD and highlight the potential to inspire future TPD approaches. © 2023 WILEY-VCH GmbH.