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
  • 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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