2. Academic Validation
  3. Design of a "Two-in-One" Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites

Design of a "Two-in-One" Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites

  • J Med Chem. 2022 Jan 27;65(2):1370-1383. doi: 10.1021/acs.jmedchem.1c00848.
Florian Wittlinger 1,  David E Heppner 2,  Ciric To 3,  Marcel Günther 1,  Bo Hee Shin 3,  Jaimin K Rana 2,  Anna M Schmoker 2,  Tyler S Beyett 2,  Lena M Berger 4 5,  Benedict-Tilman Berger 4 5,  Nicolas Bauer 4 5,  James D Vasta 6,  Cesear R Corona 6,  Matthew B Robers 6,  Stefan Knapp 4 5,  Pasi A Jänne 3 7,  Michael J Eck 2,  Stefan A Laufer 1 8 9
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Longwood Center, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.
  • 3 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Department of Medical Oncology, Department of Medicine, Harvard Medical School, Longwood Center, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.
  • 4 Structural Genomics Consortium, Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany.
  • 5 Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe University, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany.
  • 6 Promega Corporation, 2800 Woods Hollow Road, Fitchburg, Wisconsin 53711, United States.
  • 7 Belfer Center for Applied Cancer Science, Longwood Center, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.
  • 8 Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", Eberhard Karls Universität Tübingen, 72076 Tübingen, Germany.
  • 9 Tübingen Center for Academic Drug Discovery & Development (TüCAD2), 72076 Tübingen, Germany.
PMID: 34668706 DOI: 10.1021/acs.jmedchem.1c00848
Abstract

Inhibitors targeting the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung Cancer harboring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations has motivated the development of successive generations of inhibitors that bind in the ATP site. The third-generation agent osimertinib is now a first-line treatment for this disease. Recently, allosteric inhibitors have been developed to overcome drug-resistant mutations that confer a resistance to osimertinib. Here, we present the structure-guided design and synthesis of a mutant-selective lead compound, which consists of a pyridinyl imidazole-fused benzylisoindolinedione scaffold that simultaneously occupies the orthosteric and allosteric sites. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with a significantly lower activity for wild-type EGFR (47 nM). Additionally, this compound achieves modest cetuximab-independent and mutant-selective cellular efficacies on the L858R (1.2 μM) and L858R/T790M (4.4 μM) variants.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-139884
    EGFR Inhibitor