Breaking Bad Proteins – Discovery Approaches and the Road to Clinic for Degraders

Corentin Bouvier; Rachel Lawrence; Francesca Cavallo; Wendy Xolalpa; Allan Jordan; Roland Hjerpe; Manuel S Rodriguez

doi:10.20944/preprints202402.0637.v1

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preprints.org > biology and life sciences > biology and biotechnology > doi: 10.20944/preprints202402.0637.v1

Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Breaking Bad Proteins – Discovery Approaches and the Road to Clinic for Degraders

^* ,

Version 1 : Received: 10 February 2024 / Approved: 12 February 2024 / Online: 12 February 2024 (07:43:06 CET)

A peer-reviewed article of this Preprint also exists.

Bouvier, C.; Lawrence, R.; Cavallo, F.; Xolalpa, W.; Jordan, A.; Hjerpe, R.; Rodriguez, M.S. Breaking Bad Proteins—Discovery Approaches and the Road to Clinic for Degraders. Cells 2024, 13, 578. Bouvier, C.; Lawrence, R.; Cavallo, F.; Xolalpa, W.; Jordan, A.; Hjerpe, R.; Rodriguez, M.S. Breaking Bad Proteins—Discovery Approaches and the Road to Clinic for Degraders. Cells 2024, 13, 578.

Abstract

Proteolysis Targeting Chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding to a ubiquitin ligase. More generally referred to as bifunctional degraders, PROTACs have led the way in the field of targeted protein degradation (TPD) with several compounds currently undergoing clinical testing. Alongside bifunctional degraders, single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered as a viable approach for development of therapeutics, driven by advances in rational discovery approaches. This review focusses on drug discovery with respect to bifunctional and molecular glue degraders within the ubiquitin proteasome system, including analysis of mechanistic concepts and discovery approaches, with an overview of current clinical and pre-clinical degrader status in oncology, neurodegenerative and inflammatory disease.

Keywords

TPD; PROTAC; molecular glue degrader; heterobifunctional degrader; Ubiquitin; proteasome; targeted protein degradation

Subject

Biology and Life Sciences, Biology and Biotechnology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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