Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent “Type V” Kinase Inhibitors
Year: 2024
Type: article
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 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.
Source: Journal of Medicinal Chemistry
Authors: Florian Wittlinger, Surbhi P. Chitnis, Calvin D. Pham, Tahereh Damghani, Kishan B. Patel, Mareike Möllers, Ilse K. Schaeffner, Omobolanle A. Abidakun, Matthew Q. Deng, Blessing C. Ogboo, Alexander Rasch, Tyler S. Beyett, Brian Buckley, Frederic Feru, Tatiana Shaurova, Cornelius Knappe, Michael J. Eck, Pamela A. Hershberger, David A. Scott, Asher L. Brandt, Stefan A. Laufer, David E. Heppner
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
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
Awards: G1010591873, G1285306620, G1456725880, G1867732070, G2004402655, G215985982, G2408748050, G241279073, G2532469498, G2853181762, G3067052642, G3133150994, G3262563802, G357145406, G3728080647, G4594529113, G5382207646, G5765906131, Studies of mutant-selective allosteric inhibitors of EGFR for non-small cell lung cancer, G604848185, Modulation of cancer specific transcriptional factors with small molecules, G6137013498, G6476969910, G6816383395, G6985549539, G7463374569, G8701900045, G9000020627, G9000068634, G9000142182, Center for Biomolecular Structure (CBMS), Discovery and optimization of novel mutant-selective allosteric inhibitors of EGFR T790M, EXC 2180: Individualisierung von Tumortherapien durch molekulare Bildgebung und funktionelle Identifizierung therapeutischer Zielstrukturen (iFIT), G994363656
OpenAlex ID: W4404952553