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

Autor: Wittlinger F; Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany., Chitnis SP; Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States., Pham CD; Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States., Damghani T; Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States., Patel KB; Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States., Möllers M; Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany., Schaeffner IK; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States., Abidakun OA; Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States., Deng MQ; Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States., Ogboo BC; Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States., Rasch A; Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany., Beyett TS; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States., Buckley B; Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, United States., Feru F; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States., Shaurova T; Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, United States., Knappe C; Institute of Pharmaceutical Sciences, Pharmaceutical (Bio-)Analysis, University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany., Eck MJ; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States., Hershberger PA; Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, United States., Scott DA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States., Brandt AL; Department of Chemistry, University of Saint Joseph, West Hartford, Connecticut 06117 United States., Laufer SA; Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies' Eberhard Karls Universität Tübingen, 72076 Tübingen, Germany.; Tübingen Center for Academic Drug Discovery & Development (TüCAD2), 72076 Tübingen, Germany., Heppner DE; Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States.; Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, United States.; Department of Structural Biology, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Dec 12; Vol. 67 (23), pp. 21438-21469. Date of Electronic Publication: 2024 Dec 03.
DOI: 10.1021/acs.jmedchem.4c02311
Abstrakt: 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 1 / 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.
Databáze: MEDLINE
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