Structural themes of cereblon-recruiting degraders: selected recent examples
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Published on: November 9, 2020
1Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Abstract:
Targeted protein degradation is orchestrated by interactions between target proteins and components of the ubiquitin-proteasome system such as the E3 ligase cereblon. Advances in molecular visualization of the target complexes formed by cereblon have provided insights into how cereblon, degrader molecules and drug-induced non-native targets come together to enable cellular breakdown. Here, we review selected examples demonstrating how X-ray crystallography and cryogenic-electron microscopy (cryo-EM) have been applied to cereblon structures to guide the development and validation of novel preclinical heterobifunctional and molecular-glue degraders. In some instances, cryo-EM and X-ray crystallography enabled structure-guided optimization of degrader potency, while in others structural insights elucidated the molecular mechanisms underlying target specificity. Collectively, these structural studies are improving the reliability of computational predictions and paving the way for more structure-based design of cereblon-recruiting small-molecule degraders.
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