Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent “Type V” Kinase Inhibitors
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 I<sup>1</sup>/<sub>2</sub> 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.
Authors
- Pamela A. Hershberger (ORCID: https://orcid.org/0000-0003-0030-6520)
- Frédéric Féru (ORCID: https://orcid.org/0009-0000-2423-650X)
- David A. Scott (ORCID: https://orcid.org/0000-0003-3243-528X)
- Ilse K. Schaeffner
- David E. Heppner (ORCID: https://orcid.org/0000-0002-0722-5160)
- Tahereh Damghani
- Blessing C. Ogboo
- Stefan Laufer (ORCID: https://orcid.org/0000-0001-6952-1486)
- Calvin D. Pham
- Michael J. Eck (ORCID: https://orcid.org/0000-0003-4247-9403)
- Brian Buckley
- Asher L. Brandt (ORCID: https://orcid.org/0000-0002-0498-644X)
- Florian Wittlinger (ORCID: https://orcid.org/0000-0001-9028-2109)
- Kishan B. Patel (ORCID: https://orcid.org/0000-0003-4547-0447)
- Tyler S. Beyett (ORCID: https://orcid.org/0000-0001-5509-7004)
- Tatiana Shaurova
- Cornelius Knappe
- Surbhi P. Chitnis (ORCID: https://orcid.org/0000-0002-5050-2338)
- Matthew Q. Deng
- Alexander Rasch (ORCID: https://orcid.org/0009-0006-7023-3442)
- Mareike Möllers
- Omobolanle A. Abidakun (ORCID: https://orcid.org/0000-0002-2009-947X)
Institutions
- Roswell Park Comprehensive Cancer Center (US)
- Harvard University (US)
- University of Saint Joseph (US)
- Dana-Farber Cancer Institute (US)
- Bernstein Center for Computational Neuroscience Tübingen (DE)
- University at Buffalo, State University of New York (US)
- University of Tübingen (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-03
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02311
- Citations
- 6
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 1.70
Funders
- U.S. Department of Energy
- Roswell Park Cancer Institute
- Roswell Park Alliance Foundation, Roswell Park Cancer Institute
- State University of New York
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg
- National Institutes of Health
- Office of Science
- National Cancer Institute
- National Institute of General Medical Sciences
- National Center for Advancing Translational Sciences
- Biological and Environmental Research
- Brookhaven National Laboratory