2. Academic Validation
  3. Insight into Targeting Exon20 Insertion Mutations of the Epidermal Growth Factor Receptor with Wild Type-Sparing Inhibitors

Insight into Targeting Exon20 Insertion Mutations of the Epidermal Growth Factor Receptor with Wild Type-Sparing Inhibitors

  • J Med Chem. 2022 May 12;65(9):6643-6655. doi: 10.1021/acs.jmedchem.1c02080.
Jonas Lategahn 1 2 3,  Hannah L Tumbrink 4 5,  Carsten Schultz-Fademrecht 1 6,  Alena Heimsoeth 4 5,  Lisa Werr 5,  Janina Niggenaber 2 3,  Marina Keul 2 3,  Fatma Parmaksiz 4 5,  Matthias Baumann 6,  Sascha Menninger 6,  Eldar Zent 6,  Ina Landel 2 3,  Jörn Weisner 2 3,  Kirujan Jeyakumar 2 3,  Leonie Heyden 2 3,  Nicole Russ 4 5,  Fabienne Müller 4 5,  Carina Lorenz 4 5,  Johannes Brägelmann 4 5 7 8,  Inga Spille 4 5,  Tobias Grabe 2 3,  Matthias P Müller 2 3,  Johannes M Heuckmann 1,  Bert M Klebl 6 9,  Peter Nussbaumer 6,  Martin L Sos 4 5 8,  Daniel Rauh 2 3
Affiliations

Affiliations

  • 1 PearlRiver Bio GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany.
  • 2 Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44227 Dortmund, Germany.
  • 3 Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), 44227 Dortmund, Germany.
  • 4 Molecular Pathology, Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
  • 5 Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
  • 6 Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany.
  • 7 Mildred Scheel School of Oncology Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
  • 8 Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
  • 9 The Norwegian College of Fishery Science, UiT The Arctic University of Norway, PO Box 6050 Langnes, N-9037 Tromsø, Norway.
PMID: 35486541 DOI: 10.1021/acs.jmedchem.1c02080
Abstract

Despite the clinical efficacy of epidermal growth factor receptor (EGFR) inhibitors, a subset of patients with non-small cell lung Cancer displays insertion mutations in exon20 in EGFR and Her2 with limited treatment options. Here, we present the development and characterization of the novel covalent inhibitors LDC8201 and LDC0496 based on a 1H-pyrrolo[2,3-b]pyridine scaffold. They exhibited intense inhibitory potency toward EGFR and Her2 exon20 insertion mutations as well as selectivity over wild type EGFR and within the kinome. Complex crystal structures with the inhibitors and biochemical and cellular on-target activity document their favorable binding characteristics. Ultimately, we observed tumor shrinkage in mice engrafted with patient-derived EGFR-H773_V774insNPH mutant cells during treatment with LDC8201. Together, these results highlight the potential of covalent pyrrolopyridines as inhibitors to target exon20 insertion mutations.

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