2. Academic Validation
  3. A drug discovery platform to identify compounds that inhibit EGFR triple mutants

A drug discovery platform to identify compounds that inhibit EGFR triple mutants

  • Nat Chem Biol. 2020 May;16(5):577-586. doi: 10.1038/s41589-020-0484-2.
Punit Saraon  # 1,  Jamie Snider  # 1,  Yannis Kalaidzidis 2,  Leanne E Wybenga-Groot 3,  Konstantin Weiss 1,  Ankit Rai 4,  Nikolina Radulovich 5,  Luka Drecun 1 6,  Nika Vučković 1,  Adriana Vučetić 1,  Victoria Wong 1,  Brigitte Thériault 7,  Nhu-An Pham 5,  Jin H Park 8 9,  Alessandro Datti 10 11,  Jenny Wang 10,  Shivanthy Pathmanathan 1 6,  Farzaneh Aboualizadeh 1,  Anna Lyakisheva 1,  Zhong Yao 1,  Yuhui Wang 5,  Babu Joseph 7,  Ahmed Aman 7,  Michael F Moran 12 6,  Michael Prakesch 7,  Gennady Poda 7 13,  Richard Marcellus 7,  David Uehling 7,  Miroslav Samaržija 14,  Marko Jakopović 14,  Ming-Sound Tsao 5 15 16,  Frances A Shepherd 17 18,  Adrian Sacher 5,  Natasha Leighl 5,  Anna Akhmanova 4,  Rima Al-Awar 7 19,  Marino Zerial 2,  Igor Stagljar 20 21 22 23
Affiliations

Affiliations

  • 1 Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
  • 2 Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
  • 3 SPARC BioCentre, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 4 Cell Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
  • 5 Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
  • 6 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • 7 Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • 8 Department of Pharmacology and Cancer Biology Institute, Yale University, New Haven, CT, USA.
  • 9 Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
  • 10 Network Biology Collaborative Centre, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
  • 11 Department of Agriculture, Food, and Environmental Sciences, University of Perugia, Perugia, Italy.
  • 12 Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, Ontario, Canada.
  • 13 Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
  • 14 Department for Lung Diseases Jordanovac, Clinical Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia.
  • 15 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • 16 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
  • 17 Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • 18 Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
  • 19 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
  • 20 Donnelly Centre, University of Toronto, Toronto, Ontario, Canada. igor.stagljar@utoronto.ca.
  • 21 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. igor.stagljar@utoronto.ca.
  • 22 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada. igor.stagljar@utoronto.ca.
  • 23 Mediterranean Institute for Life Sciences, Split, Croatia. igor.stagljar@utoronto.ca.
  • # Contributed equally.
PMID: 32094923 DOI: 10.1038/s41589-020-0484-2
Abstract

Receptor Tyrosine Kinases (RTKs) are transmembrane receptors of great clinical interest due to their role in disease. Historically, therapeutics targeting RTKs have been identified using in vitro kinase assays. Due to frequent development of drug resistance, however, there is a need to identify more diverse compounds that inhibit mutated but not wild-type RTKs. Here, we describe MaMTH-DS (mammalian membrane two-hybrid drug screening), a live-cell platform for high-throughput identification of small molecules targeting functional protein-protein interactions of RTKs. We applied MaMTH-DS to an oncogenic epidermal growth factor receptor (EGFR) mutant resistant to the latest generation of clinically approved tyrosine kinase inhibitors (TKIs). We identified four mutant-specific compounds, including two that would not have been detected by conventional in vitro kinase assays. One of these targets mutant EGFR via a new mechanism of action, distinct from classical TKI inhibition. Our results demonstrate how MaMTH-DS is a powerful complement to traditional drug screening approaches.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-138072
    99.78%, EGFR抑制剂
  • HY-131067
    99.72%, EGFR Triple Mutant 抑制剂
  • HY-131066
    99.02%, EGFR Triple Mutant 抑制剂
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