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Identification of Small Molecule-binding Proteins in a Native Cellular Environment by Live-cell Photoaffinity Labeling
Published on: September 20, 2016
Target discovery in small-molecule cell-based screens by in situ proteome reactivity profiling
Michael J Evans1, Alan Saghatelian, Erik J Sorensen
1The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Nature Biotechnology
|October 4, 2005
Summary
Researchers developed a novel small-molecule library to identify drug targets. Compound MJE3 selectively inhibited phosphoglycerate mutase 1 (PGAM1), a key enzyme in cancer cell glycolysis, revealing its therapeutic potential.
Area of Science:
- Biochemistry
- Chemical Biology
- Oncology
Background:
- Identifying protein targets of bioactive compounds is crucial for chemical genomics.
- Existing methods face challenges in determining molecular targets within living systems.
Purpose of the Study:
- To develop a novel approach for identifying small-molecule targets in chemical genomics.
- To discover novel inhibitors of breast cancer cell proliferation and their protein targets.
Main Methods:
- Creation of a natural product-inspired small-molecule library with protein-reactive elements.
- Cell-based screening to identify compounds inhibiting breast cancer cell proliferation.
- In situ proteome reactivity profiling to determine direct protein targets of active compounds.
Main Results:
- A compound, MJE3, was identified that inhibits breast cancer cell proliferation.
- MJE3 was found to covalently label and inhibit the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) exclusively in intact cells.
- PGAM1 inhibition by MJE3 supports the role of glycolysis in cancer cell viability.
Conclusions:
- The developed library and screening approach enable target identification of bioactive small molecules in living systems.
- PGAM1 is a potential therapeutic target for breast cancer, given its essential role in cancer cell glycolysis.
- Protein-reactive compounds are valuable tools for chemical genomics and drug discovery.
