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Design and Applications of Bifunctional Small Molecules: Why Two Heads Are Better Than One

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Department of Molecular, Cellular & Developmental Biology
Departments of Chemistry and Pharmacology, Yale University, New Haven, Connecticut 06511
* Corresponding author, [email protected]
§These authors contributed equally to this work.
Cite this: ACS Chem. Biol. 2008, 3, 11, 677–692
Publication Date (Web):October 23, 2008
https://doi.org/10.1021/cb8001792
Copyright © 2008 American Chemical Society

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    Abstract

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    Induction of protein−protein interactions is a daunting challenge, but recent studies show promise for small molecules that specifically bring two or more protein molecules together for enhanced or novel biological effect. The first such bifunctional molecules were the rapamycin- and FK506-based “chemical inducers of dimerization”, but the field has since expanded with new molecules and new applications in chemical genetics and cell biology. Examples include coumermycin-mediated gyrase B dimerization, proteolysis targeting chimeric molecules (PROTACs), drug hybrids, and strategies for exploiting multivalency in toxin binding and antibody recruitment. This Review discusses these and other advances in the design and use of bifunctional small molecules and potential strategies for future systems.

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