Abstract
Nature uses a variety of tools to mediate the flow of information in cells, many of which control distances between key biomacromolecules. Researchers have thus generated compounds whose activities stem from interactions with two (or more) proteins simultaneously. In this Perspective, we describe how these ‘bifunctional’ small molecules facilitate the study of an increasingly wide range of complex biological phenomena and enable the drugging of otherwise challenging therapeutic targets and processes. Despite their structural and functional differences, all bifunctional molecules employ Nature’s strategy of altering interactomes and inducing proximity to modulate biology. They therefore exhibit a shared set of chemical and biophysical principles that have not yet been appreciated fully. By highlighting these commonalities—and their wide-ranging consequences—we hope to chip away at the artificial barriers that threaten to constrain this interdisciplinary field. Doing so promises to yield remarkable benefits for biological research and therapeutics discovery.
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Acknowledgements
The authors thank B. Melillo, J. Ostrem, and B. Wagner for their critical feedback on the manuscript. Research from the Schreiber laboratory in the area covered by this Perspective was generously supposed by the National Institute of General Medical Sciences.
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S.L.S. serves on the Board of Directors of the Genomics Institute of the Novartis Research Foundation (“GNF”); is a shareholder and serves on the Board of Directors of Jnana Therapeutics; is a shareholder of Forma Therapeutics; is a shareholder and advises Decibel Therapeutics and Eikonizo Therapeutics; serves on the Scientific Advisory Boards of Eisai Co., Ltd., Ono Pharma Foundation, Exo Therapeutics, and F-Prime Capital Partners; and is a Novartis Faculty Scholar. C.J.G. is an employee of Vertex Pharmaceuticals.
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Gerry, C.J., Schreiber, S.L. Unifying principles of bifunctional, proximity-inducing small molecules. Nat Chem Biol 16, 369–378 (2020). https://doi.org/10.1038/s41589-020-0469-1
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DOI: https://doi.org/10.1038/s41589-020-0469-1
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