Deciphering the Structure−Activity Relationships Underpinning the Linkerology of Bivalent EGFR Inhibitors

Abstract Linking small molecules that bind adjacent sites on a target is a promising strategy for developing compounds with tight binding affinities. ATP-allosteric bivalent inhibitors (AABIs) of the epidermal growth factor receptor (EGFR) have provided new insights into efficient linker design where large potency gains can be achieved through particular design scenarios. In this work, we systematically evaluated the structure−activity relationships of target molecules to better understand the most effective approach to maximizing potency through linker optimization. Our results show that linker length and points of connection are both important strategies for significant potency enhancements. Structures and simulations indicate that maximal flexibility is likely the most important design criterion for linking molecules that occupy adjacent pockets, as modeled by the EGFR kinase domain. These studies provide a general framework for the rational design of linkers broadly relevant to fragment-based drug discovery and a number of related scenarios in medicinal chemistry.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2026-10-09
DOI
https://doi.org/10.1021/acs.jmedchem.6c02714
Primary Topic
Computational Drug Discovery Methods
Type
article
Field-Weighted Citation Impact
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article

Deciphering the Structure−Activity Relationships Underpinning the Linkerology of Bivalent EGFR Inhibitors

David E. Heppner, Blessing C. Ogboo, Stefan Laufer, Monica R. MacDonald et al.
Journal of Medicinal Chemistry
Computational Drug Discovery Methods
article

Deciphering the Structure−Activity Relationships Underpinning the Linkerology of Bivalent EGFR Inhibitors

David E. Heppner, Blessing C. Ogboo, Stefan Laufer, Monica R. MacDonald, Michael J. Eck, Stephen J. Collins, Asher L. Brandt, Florian Wittlinger, Ishola Abeeb Akinwumi, Nader N. Nasief, Kishan B. Patel, Surbhi P. Chitnis, Hung Tan Nguyen, Omobolanle A. Abidakun, Emily A. Ouellette, Colton L. Zack, Tess M. Weber
article en

Abstract

Abstract Linking small molecules that bind adjacent sites on a target is a promising strategy for developing compounds with tight binding affinities. ATP-allosteric bivalent inhibitors (AABIs) of the epidermal growth factor receptor (EGFR) have provided new insights into efficient linker design where large potency gains can be achieved through particular design scenarios. In this work, we systematically evaluated the structure−activity relationships of target molecules to better understand the most effective approach to maximizing potency through linker optimization. Our results show that linker length and points of connection are both important strategies for significant potency enhancements. Structures and simulations indicate that maximal flexibility is likely the most important design criterion for linking molecules that occupy adjacent pockets, as modeled by the EGFR kinase domain. These studies provide a general framework for the rational design of linkers broadly relevant to fragment-based drug discovery and a number of related scenarios in medicinal chemistry.

Journal of Medicinal Chemistry
Roswell Park Comprehensive Cancer Center (US), Harvard University (US), German Cancer Research Center (DE), University of Saint Joseph (US), Dana-Farber Cancer Institute (US), National Organization for Drug Control and Research (EG), University at Buffalo, State University of New York (US), University of Tübingen (DE)
Openalex Percentile: Top 13%
Computational Drug Discovery Methods
DOIOpen Access PDFOpenAlex
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