2. Academic Validation
  3. Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors

Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors

  • Commun Chem. 2024 Feb 20;7(1):38. doi: 10.1038/s42004-024-01108-3.
Florian Wittlinger # 1,  Blessing C Ogboo # 2,  Ekaterina Shevchenko 1 3 4,  Tahereh Damghani 2,  Calvin D Pham 2,  Ilse K Schaeffner 5 6,  Brandon T Oligny 2,  Surbhi P Chitnis 2,  Tyler S Beyett 5 6 7,  Alexander Rasch 1,  Brian Buckley 8,  Daniel A Urul 9,  Tatiana Shaurova 10,  Earl W May 9,  Erik M Schaefer 9,  Michael J Eck 5 6,  Pamela A Hershberger 10,  Antti Poso 1 3 4 11,  Stefan A Laufer 12 13 14,  David E Heppner 15 16 17
Affiliations

Affiliations

  • 1 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
  • 2 Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA.
  • 3 Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies" Eberhard Karls Universität Tübingen, 72076, Tübingen, Germany.
  • 4 Tübingen Center for Academic Drug Discovery & Development (TüCAD2), 72076, Tübingen, Germany.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 6 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
  • 7 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 5119 Rollins Research Center, 1510 Clifton Rd, Atlanta, GA, 30322, USA.
  • 8 Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14203, USA.
  • 9 AssayQuant Technologies, Inc., Marlboro, MA, 01752, USA.
  • 10 Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14203, USA.
  • 11 School of Pharmacy, University of Eastern Finland, 70210, Kuopio, Finland.
  • 12 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany. stefan.laufer@uni-tuebingen.de.
  • 13 Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies" Eberhard Karls Universität Tübingen, 72076, Tübingen, Germany. stefan.laufer@uni-tuebingen.de.
  • 14 Tübingen Center for Academic Drug Discovery & Development (TüCAD2), 72076, Tübingen, Germany. stefan.laufer@uni-tuebingen.de.
  • 15 Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA. davidhep@buffalo.edu.
  • 16 Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14203, USA. davidhep@buffalo.edu.
  • 17 Department of Structural Biology, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA. davidhep@buffalo.edu.
  • # Contributed equally.
PMID: 38378740 DOI: 10.1038/s42004-024-01108-3
Abstract

Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to the dual motif architecture of these molecules and the variability that can be introduced through differing linker structures and geometries. We report a set of alternatively linked bivalent EGFR inhibitors that simultaneously occupy the ATP substrate and allosteric pockets. Crystal structures show that initial and redesigned linkers bridging a trisubstituted imidazole ATP-site inhibitor and dibenzodiazepinone allosteric-site inhibitor proved successful in spanning these sites. The re-engineered linker yielded a compound that exhibited significantly higher potency (~60 pM) against the drug-resistant EGFR L858R/T790M and L858R/T790M/C797S, which was superadditive as compared with the parent molecules. The enhanced potency is attributed to factors stemming from the linker connection to the allosteric-site group and informs strategies to engineer linkers in bivalent agent design.

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