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Small molecule probes for targeting autophagy

Abstract

Autophagy is implicated in a wide range of (patho)physiological processes including maintenance of cellular homeostasis, neurodegenerative disorders, aging and cancer. As such, small molecule autophagy modulators are in great demand, both for their ability to act as tools to better understand this essential process and as potential therapeutics. Despite substantial advances in the field, major challenges remain in the development and comprehensive characterization of probes that are specific to autophagy. In this Review, we discuss recent developments in autophagy-modulating small molecules, including the specific challenges faced in the development of activators and inhibitors, and recommend guidelines for their use. Finally, we discuss the potential to hijack the process for targeted protein degradation, an area of great importance in chemical biology and drug discovery.

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Fig. 1: Overview of the autophagy process.
Fig. 2: Small molecules inducing autophagy.
Fig. 3: Small molecule inhibitors of autophagy initiation.
Fig. 4: Small molecules inhibiting lysosomal activity.
Fig. 5: Targeted protein degradation using autophagosomes and lysosomes.

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Acknowledgements

We gratefully acknowledge the Novo Nordisk Foundation, the Independent Research Fund Denmark, the Carlsberg Foundation and DTU for financial support to L.L. T.W.-E. acknowledges DTU for a PhD fellowship.

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Peer review information Nature Chemical Biology thanks Sovan Sarkar and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Whitmarsh-Everiss, T., Laraia, L. Small molecule probes for targeting autophagy. Nat Chem Biol 17, 653–664 (2021). https://doi.org/10.1038/s41589-021-00768-9

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