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Nat Chem Biol. 2016 Apr;12(4):275-81. doi: 10.1038/nchembio.2026. Epub 2016 Feb 22.

Pooled screening for antiproliferative inhibitors of protein-protein interactions.

Author information

1
Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
2
Department of Chemistry, Biomedical Center (BMC), Uppsala University, Uppsala, Sweden.
3
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
4
Canadian Institute for Advanced Research, Toronto, Ontario, Canada.
5
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, Maryland, USA.
6
Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.

Abstract

Protein-protein interactions (PPIs) are emerging as a promising new class of drug targets. Here, we present a novel high-throughput approach to screen inhibitors of PPIs in cells. We designed a library of 50,000 human peptide-binding motifs and used a pooled lentiviral system to express them intracellularly and screen for their effects on cell proliferation. We thereby identified inhibitors that drastically reduced the viability of a pancreatic cancer line (RWP1) while leaving a control line virtually unaffected. We identified their target interactions computationally, and validated a subset in experiments. We also discovered their potential mechanisms of action, including apoptosis and cell cycle arrest. Finally, we confirmed that synthetic lipopeptide versions of our inhibitors have similarly specific and dosage-dependent effects on cancer cell growth. Our screen reveals new drug targets and peptide drug leads, and it provides a rich data set covering phenotypes for the inhibition of thousands of interactions.

PMID:
26900867
PMCID:
PMC5756068
DOI:
10.1038/nchembio.2026
[Indexed for MEDLINE]
Free PMC Article

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