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A synthetic library of cell-permeable molecules
K Koide1, J M Finkelstein, Z Ball
1Contribution from the Department of Chemistry and Chemical Biology, Institute of Chemistry and Cell Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
Journal of the American Chemical Society
|July 18, 2001
Summary
Researchers developed novel synthetic heterodimerizers by linking a known ligand to a diverse library of tetrahydrooxazepines. These molecules can induce protein associations, enabling new biological discoveries in cells.
Area of Science:
- Chemical biology
- Molecular pharmacology
- Drug discovery
Background:
- Small molecules that modulate macromolecular interactions are valuable tools in biological research.
- Current methods rely on known ligands for well-characterized proteins, limiting broader applications.
- There is a need for novel heterodimerizers targeting proteins without established ligands or inducing new biological responses.
Purpose of the Study:
- To construct a diversified library of synthetic heterodimerizers.
- To enable the discovery of novel biological responses using chemical inducers of dimerization.
- To broaden the applicability of small molecules in modulating protein-protein interactions.
Main Methods:
- Synthesis of 320 substituted tetrahydrooxazepines (THOXs) using Mitsonobu displacements and olefin metathesis.
- Coupling of THOXs to a constant ligand targeting FK506-binding protein (AP1867).
- Parallel synthesis and purification of candidate heterodimerizers for biological testing.
Main Results:
- A library of 320 synthetic heterodimerizers was successfully constructed.
- Candidate heterodimerizers were produced in sufficient yield and purity for direct biological use.
- A panel of 25 heterodimerizers demonstrated membrane permeability and activity in human fibrosarcoma cells.
Conclusions:
- The developed synthetic strategy allows for the creation of diverse heterodimerizer libraries.
- These novel small molecules can induce dimerization and modulate biological processes in intact cells.
- This approach opens new avenues for exploring novel biological functions and therapeutic targets.
