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

• Published in: Nature chemical biology Vol. 16; no. 5; pp. 577 - 586
• Main Authors: Saraon, Punit, Snider, Jamie, Kalaidzidis, Yannis, Wybenga-Groot, Leanne E., Weiss, Konstantin, Rai, Ankit, Radulovich, Nikolina, Drecun, Luka, Vučković, Nika, Vučetić, Adriana, Wong, Victoria, Thériault, Brigitte, Pham, Nhu-An, Park, Jin H., Datti, Alessandro, Wang, Jenny, Pathmanathan, Shivanthy, Aboualizadeh, Farzaneh, Lyakisheva, Anna, Yao, Zhong, Wang, Yuhui, Joseph, Babu, Aman, Ahmed, Moran, Michael F., Prakesch, Michael, Poda, Gennady, Marcellus, Richard, Uehling, David, Samaržija, Miroslav, Jakopović, Marko, Tsao, Ming-Sound, Shepherd, Frances A., Sacher, Adrian, Leighl, Natasha, Akhmanova, Anna, Al-awar, Rima, Zerial, Marino, Stagljar, Igor
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2020; Nature Publishing Group
• Subjects: 631/67; 631/92/275; 631/92/507; 631/92/613; Automation; Biochemical Engineering; Biochemistry; Biology; Bioorganic Chemistry; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Cell Biology; Cell Line; Cell Line, Tumor; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; DNA Nucleotidyltransferases - genetics; Drug Discovery; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug screening; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; Genes, Reporter; Growth factors; Health care networks; High-Throughput Screening Assays - methods; Hospitals; Humans; Inhibitors; Kinases; Ligands; Luciferases - genetics; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Medical research; Mutants; Mutation; Pharmacology; Phosphorylation - drug effects; Protein interaction; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Proteins; R&D; Receptors; Reproducibility of Results; Research & development; Resistance factors; Screening; Small Molecule Libraries - pharmacology; Staurosporine - analogs & derivatives; Staurosporine - pharmacology; Tyrosine
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/s41589-020-0484-2

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. A high-throughput small-molecule drug screening platform enabled the detection of compounds targeting the functional interactions of receptor tyrosine kinases and identifies four new EGFR triple-mutant inhibitors.