Unifying principles of bifunctional, proximity-inducing small molecules
Open accessAbstract
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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Some of the best-studied small molecules such as rapamycin, FK506, or cyclosporin function via stabilizing non-natural protein-protein interactions.
“Some of the best-studied small-molecules such as rapamycin, FK506, or cyclosporin function via stabilizing non-natural protein–protein interactions.25”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [25]
Structurally diverse degraders can prompt ternary assemblies of different architectures.
“Enabled by the plasticity of a given protein-protein interface, structurally diverse degraders can prompt ternary assemblies of different architectures2,9.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [2]
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Schreiber, S. L. (2021) · Cell · doi:10.1016/j.cell.2020.12.020 · Cited by 598 · see citing works
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- Authors
- Gerry, C. J., & Schreiber, S. L.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Schreiber, Stuart L.
- ORCID
- Schreiber, Stuart L.
- Venue
- Nature Chemical Biology
- Published
- 2020-03-20
- Volume
- 16
- Issue
- 4
- Pages
- 369-378
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC7312755
- OpenAlex
- W3012278138
- Cited by
- 199
- References
- 102
- Citations by year
- 2026: 22 · 2025: 38 · 2024: 28 · 2023: 36 · 2022: 34 · 2021: 27 · 2020: 14
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R35GM127045)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Biotin and Related Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- bifunctional small molecules, protein-protein interaction, protein-protein interaction inhibitors, drug discovery, biophysical principles, biological mechanisms
- MeSH terms
- Animals, Humans, Protein Binding, Proteins, Structure-Activity Relationship, Protein Interaction Domains and Motifs, Small Molecule Libraries
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