دورية أكاديمية
Insight into Targeting Exon20 Insertion Mutations of the Epidermal Growth Factor Receptor with Wild Type-Sparing Inhibitors.
| العنوان: | Insight into Targeting Exon20 Insertion Mutations of the Epidermal Growth Factor Receptor with Wild Type-Sparing Inhibitors. |
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| المؤلفون: | Lategahn J; PearlRiver Bio GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany.; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44227 Dortmund, Germany.; Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), 44227 Dortmund, Germany., Tumbrink HL; Molecular Pathology, Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany., Schultz-Fademrecht C; PearlRiver Bio GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany.; Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany., Heimsoeth A; Molecular Pathology, Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany., Werr L; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany., Niggenaber J; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44227 Dortmund, Germany.; Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), 44227 Dortmund, Germany., Keul M; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44227 Dortmund, Germany.; Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), 44227 Dortmund, Germany., Parmaksiz F; Molecular Pathology, Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany., Baumann M; Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany., Menninger S; Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany., Zent E; Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany., Landel I; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44227 Dortmund, Germany.; Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), 44227 Dortmund, Germany., Weisner J; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44227 Dortmund, Germany.; Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), 44227 Dortmund, Germany., Jeyakumar K; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44227 Dortmund, Germany.; Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), 44227 Dortmund, Germany., Heyden L; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44227 Dortmund, Germany.; Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), 44227 Dortmund, Germany., Russ N; Molecular Pathology, Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany., Müller F; Molecular Pathology, Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany., Lorenz C; Molecular Pathology, Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany., Brägelmann J; Molecular Pathology, Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Mildred Scheel School of Oncology Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany., Spille I; Molecular Pathology, Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany., Grabe T; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44227 Dortmund, Germany.; Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), 44227 Dortmund, Germany., Müller MP; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44227 Dortmund, Germany.; Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), 44227 Dortmund, Germany., Heuckmann JM; PearlRiver Bio GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany., Klebl BM; Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany.; The Norwegian College of Fishery Science, UiT The Arctic University of Norway, PO Box 6050 Langnes, N-9037 Tromsø, Norway., Nussbaumer P; Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany., Sos ML; Molecular Pathology, Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany., Rauh D; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44227 Dortmund, Germany.; Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), 44227 Dortmund, Germany. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2022 May 12; Vol. 65 (9), pp. 6643-6655. Date of Electronic Publication: 2022 Apr 29. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Carcinoma, Non-Small-Cell Lung*/drug therapy , Lung Neoplasms*/drug therapy , Lung Neoplasms*/genetics , Lung Neoplasms*/pathology, Animals ; Humans ; Mice ; Mutagenesis, Insertional ; Mutation ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use |
| مستخلص: | 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 1 H -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. |
| المشرفين على المادة: | 0 (Protein Kinase Inhibitors) |
| تواريخ الأحداث: | Date Created: 20220429 Date Completed: 20220517 Latest Revision: 20220529 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1021/acs.jmedchem.1c02080 |
| PMID: | 35486541 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.1c02080 |