title: Pooled screening for antiproliferative inhibitors of protein-protein interactions.
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.
authors.affiliation: Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Satra
authors.initials: S
authors.lastname: Nim
authors.affiliation: Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jouhyun
authors.initials: J
authors.lastname: Jeon
authors.affiliation: Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Carles
authors.initials: C
authors.lastname: Corbi-Verge
authors.affiliation: Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Moon-Hyeong
authors.initials: MH
authors.lastname: Seo
authors.affiliation: Department of Chemistry, Biomedical Center (BMC), Uppsala University, Uppsala, Sweden.
authors.forename: Ylva
authors.identifier: http://orcid.org/0000-0002-7081-3846
authors.initials: Y
authors.lastname: Ivarsson
authors.affiliation: Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|Canadian Institute for Advanced Research, Toronto, Ontario, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Moffat
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, Maryland, USA.
authors.forename: Nadya
authors.initials: N
authors.lastname: Tarasova
authors.affiliation: Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003001:Cloning, Molecular; D055808:Drug Discovery / Q000379:methods*; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D019151:Peptide Library; D025941:Protein Interaction Mapping / Q000379:methods*; D060066:Protein Interaction Maps / Q000187:drug effects* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D019151:Peptide Library