Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent "Type V" Kinase Inhibitors

  • J Med Chem. 2024 Dec 12;67(23):21438-21469. doi: 10.1021/acs.jmedchem.4c02311.
Florian Wittlinger  1 ,  Surbhi P Chitnis  2 ,  Calvin D Pham  2 ,  Tahereh Damghani  2 ,  Kishan B Patel  2 ,  Mareike Möllers  1 ,  Ilse K Schaeffner  3  4 ,  Omobolanle A Abidakun  2 ,  Matthew Q Deng  2 ,  Blessing C Ogboo  2 ,  Alexander Rasch  1 ,  Tyler S Beyett  3  4 ,  Brian Buckley  5 ,  Frederic Feru  3  4 ,  Tatiana Shaurova  6 ,  Cornelius Knappe  7 ,  Michael J Eck  3  4 ,  Pamela A Hershberger  6 ,  David A Scott  3  4 ,  Asher L Brandt  8 ,  Stefan A Laufer  1  9  10 ,  David E Heppner  2  6  11
Affiliations
  • 1. Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
  • 2. Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States.
  • 3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • 5. Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, United States.
  • 6. Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, United States.
  • 7. Institute of Pharmaceutical Sciences, Pharmaceutical (Bio-)Analysis, University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
  • 8. Department of Chemistry, University of Saint Joseph, West Hartford, Connecticut 06117 United States.
  • 9. Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies" Eberhard Karls Universität Tübingen, 72076 Tübingen, Germany.
  • 10. Tübingen Center for Academic Drug Discovery & Development (TüCAD2), 72076 Tübingen, Germany.
  • 11. Department of Structural Biology, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States.
PMID: 39626019 DOI: 10.1021/acs.jmedchem.4c02311
Abstract

Binding multiple sites within proteins with bivalent compounds is a strategy for developing uniquely active agents. A new class of dual-site inhibitors has emerged targeting the epidermal growth factor receptor (EGFR) anchored to both the orthosteric (ATP) and allosteric sites. Despite proof-of-concept successes, enabling selectivity against oncogenic activating mutations has not been achieved and classifying these inhibitors among kinase inhibitors remains underexplored. This study investigates the structure-activity relationships, binding modes, and biological activity of ATP-allosteric bivalent inhibitors (AABIs). We find that AABIs selectively inhibit drug-resistant EGFR mutants (L858R/T790M and L858R/T790M/C797S) by anchoring a methyl isoindolinone moiety along the αC-helix channel of the allosteric site. In contrast, related Type I1/2 inhibitors target wild-type EGFR but are less effective against resistant mutants. This shift in selectivity demonstrates that mutant-selective AABIs classify as "Type V" bivalent inhibitors.

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