Format

Send to

Choose Destination
Nat Chem Biol. 2020 Feb 24. doi: 10.1038/s41589-020-0484-2. [Epub ahead of print]

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

Author information

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.

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.

PMID:
32094923
DOI:
10.1038/s41589-020-0484-2

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center