Journal Article

DKFZ-2026-02675

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Deciphering the Structure-Activity Relationships Underpinning the Linkerology of Bivalent EGFR Inhibitors.

Patel, K. B. ; Akinwumi, I. A. ; Weber, T. M. ; MacDonald, M. R. ; Collins, S. J. ; Chitnis, S. P. ; Zack, C. L. ; Ogboo, B. C. ; Nasief, N. N. ; Ouellette, E. A. ; Abidakun, O. A. ; Eck, M. J. ; Brandt, A. L. ; Wittlinger, F. ; Laufer, S. A.DKFZ* ; Nguyen, H. T. ; Heppner, D. E.

2026
ACS Washington, DC

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.

Keyword(s): ErbB Receptors: antagonists & inhibitors (MeSH) ; ErbB Receptors: chemistry (MeSH) ; ErbB Receptors: metabolism (MeSH) ; Structure-Activity Relationship (MeSH) ; Protein Kinase Inhibitors: chemistry (MeSH) ; Protein Kinase Inhibitors: pharmacology (MeSH) ; Humans (MeSH) ; Models, Molecular (MeSH) ; Drug Design (MeSH) ; ErbB Receptors ; Protein Kinase Inhibitors ; EGFR protein, human

Note: #NCTZFB26#

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Contributing Institute(s):

1. Koordinierungsstelle NCT SüdWest (SW01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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