Targeted protein degradation as a powerful research tool in basic biology and drug target discovery

Abstract

Controlled perturbation of protein activity is essential to study protein function in cells and living organisms. Small molecules that hijack the cellular protein ubiquitination machinery to selectively degrade proteins of interest, so-called degraders, have recently emerged as alternatives to selective chemical inhibitors, both as therapeutic modalities and as powerful research tools. These systems offer unprecedented temporal and spatial control over protein function. Here, we review recent developments in this field, with a particular focus on the use of degraders as research tools to interrogate complex biological problems.

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Fig. 1: Schematic representations of key concepts in protein degradation.
Fig. 2: An overview of degradation tag fusion strategies for targeted protein degradation.
Fig. 3: Schematic representations of targeted protein degradation strategies mediated by macromolecular conjugates.
Fig. 4: Validation methods for targeted protein degradation at different stages of the ubiquitin–proteasome pathway.

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Acknowledgements

We thank all members of the Fischer lab for discussions and insights. This work was supported by NIH grants NCI R01CA214608 and R01CA218278 (to E.S.F.) and a Mark Foundation Emerging Leader Award (to E.S.F.). E.S.F. is a Damon Runyon-Rachleff Innovator supported in part by the Damon Runyon Cancer Research Foundation (DRR-50–18). H.Y. is supported by a Chleck Foundation fellowship.

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T.W., H.Y., Y.X., S.D-C., R.P.N. and E.S.F. contributed to writing the manuscript and preparing display items and have approved the final version of the manuscript.

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Correspondence to Eric S. Fischer.

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E.S.F. is a founder, scientific advisory board (SAB) member and equity holder of Civetta Therapeutics. E.S.F. is a SAB member and equity holder of C4 Therapeutics. E.S.F. is or has consulted for Novartis, AbbVie, Astellas, Deerfield, EcoR1 and Pfizer. The Fischer lab receives or has received research funding from Novartis, Deerfield and Astellas.

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Wu, T., Yoon, H., Xiong, Y. et al. Targeted protein degradation as a powerful research tool in basic biology and drug target discovery. Nat Struct Mol Biol (2020). https://doi.org/10.1038/s41594-020-0438-0

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