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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.
Obst-Sander, Ulrike; Ricci, Antonio; Kuhn, Bernd; Friess, Thomas; Koldewey, Philipp; Kuglstatter, Andreas; Hewings, David; Goergler, Annick; Steiner, Sandra; Rueher, Daniel; Imhoff, Marie-Paule; Raschetti, Noemi; Marty, Hans-Peter; Dietzig, Aline; Rynn, Caroline; Ehler, Andreas; Burger, Dominique; Kornacker, Martin; Schaffland, Jeannine Petrig; Herting, Frank; Pao, William; Bischoff, James R; Martoglio, Bruno; Alice Nagel, Yvonne; Jaeschke, Georg.
Afiliación
  • Obst-Sander U; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Ricci A; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Kuhn B; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Friess T; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Discovery Oncology, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, Penzberg82377, Germany.
  • Koldewey P; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Kuglstatter A; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Hewings D; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Goergler A; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Steiner S; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Rueher D; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Imhoff MP; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Raschetti N; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Marty HP; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Dietzig A; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Cancer Targeted Therapies, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Rynn C; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Ehler A; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Burger D; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Kornacker M; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Clinical Development Oncology, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Schaffland JP; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Herting F; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Discovery Oncology, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, Penzberg82377, Germany.
  • Pao W; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Bischoff JR; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Cancer Targeted Therapies, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Martoglio B; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Cancer Targeted Therapies, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Alice Nagel Y; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Cancer Targeted Therapies, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
  • Jaeschke G; F. Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel4070, Switzerland.
J Med Chem ; 65(19): 13052-13073, 2022 10 13.
Article en En | MEDLINE | ID: mdl-36178776
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Pulmón de Células no Pequeñas / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Pulmón de Células no Pequeñas / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos