Discovery of Novel Allosteric EGFR L858R Inhibitors for the Treatment of Non-Small-Cell Lung Cancer as a Single Agent or in Combination with Osimertinib

  • J Med Chem. 2022 Oct 13;65(19):13052-13073. doi: 10.1021/acs.jmedchem.2c00893.
Ulrike Obst-Sander  1 ,  Antonio Ricci  1 ,  Bernd Kuhn  1 ,  Thomas Friess  2 ,  Philipp Koldewey  1 ,  Andreas Kuglstatter  1 ,  David Hewings  1 ,  Annick Goergler  1 ,  Sandra Steiner  1 ,  Daniel Rueher  1 ,  Marie-Paule Imhoff  1 ,  Noemi Raschetti  1 ,  Hans-Peter Marty  1 ,  Aline Dietzig  3 ,  Caroline Rynn  4 ,  Andreas Ehler  1 ,  Dominique Burger  1 ,  Martin Kornacker  5 ,  Jeannine Petrig Schaffland  1 ,  Frank Herting  2 ,  William Pao  6 ,  James R Bischoff  3 ,  Bruno Martoglio  3 ,  Yvonne Alice Nagel  3 ,  Georg Jaeschke  1
Affiliations
  • 1. F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • 2. F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Discovery Oncology, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, Penzberg82377, Germany.
  • 3. F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Cancer Targeted Therapies, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • 4. F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • 5. F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Clinical Development Oncology, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • 6. F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
PMID: 36178776 DOI: 10.1021/acs.jmedchem.2c00893
Abstract

Addressing resistance to third-generation EGFR TKIs such as osimertinib via the EGFRC797S mutation remains a highly unmet need in EGFR-driven non-small-cell lung Cancer (NSCLC). Herein, we present the discovery of the allosteric EGFR Inhibitor 57, a novel fourth-generation inhibitor to overcome EGFRC797S-mediated resistance in patients harboring the activating EGFRL858R mutation. 57 exhibits an improved potency compared to previous allosteric EGFR inhibitors. To our knowledge, 57 is the first allosteric EGFR Inhibitor that demonstrates robust tumor regression in a mutant EGFRL858R/C797S tumor model. Additionally, 57 is active in an H1975 EGFRL858R/T790M NSCLC xenograft model and shows superior efficacy in combination with osimertinib compared to the single agents. Our data highlight the potential of 57 as a single agent against EGFRL858R/C797S and EGFRL858R/T790M/C797S and as combination therapy for EGFRL858R- and EGFRL858R/T790M-driven NSCLC.