Issue 15, 2022

Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders

Abstract

Progress in strategies aimed at breaking down therapeutic target proteins has led to a paradigm shift in drug discovery. Thalidomide and its derivatives are the only protein degraders currently used in clinical practice. Our understanding of the molecular mechanism of action of thalidomide and its derivatives has advanced dramatically since the identification of cereblon (CRBN) as their direct target. The binding of thalidomide derivatives to CRBN, a substrate recognition receptor for Cullin 4 RING E3 ubiquitin ligase (CRL4), induces the recruitment of non-native substrates to CRL4CRBN and their subsequent degradation. This discovery was a breakthrough in the current rapid development of protein-degrading agents because clarification of the mechanism of action of thalidomide derivatives has demonstrated the clinical value of these compounds. This review provides an overview of the mechanism of action of thalidomide and its derivatives and describes perspectives for protein degraders.

Graphical abstract: Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders

Article information

Article type
Tutorial Review
Submitted
08 feb 2022
First published
07 jul 2022
This article is Open Access
Creative Commons BY-NC license

Chem. Soc. Rev., 2022,51, 6234-6250

Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders

J. Yamamoto, T. Ito, Y. Yamaguchi and H. Handa, Chem. Soc. Rev., 2022, 51, 6234 DOI: 10.1039/D2CS00116K

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