2. Academic Validation
  3. Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent "Type V" Kinase Inhibitors

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

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.

Figures
Products