Discovery of a Highly Potent and Broadly Effective Epidermal Growth Factor Receptor and HER2 Exon 20 Insertion Mutant Inhibitor
| Autor: | Jamie A. Saxon, Michael J. Eck, Pasi A. Jänne, T. Kosaka, Jieun Son, Eun Young Park, Hwan Geun Choi, Nathanael S. Gray, Dries De Clercq, Jaebong Jang, Junko Tanizaki |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Lung Neoplasms Receptor ErbB-2 Afatinib Mutant Biology medicine.disease_cause Article Catalysis 03 medical and health sciences Exon 0302 clinical medicine Cell Line Tumor medicine Humans Epidermal growth factor receptor Protein Kinase Inhibitors Cell Proliferation Mutation Wild type Exons General Medicine General Chemistry Activating mutation ErbB Receptors Fluorobenzenes Molecular Docking Simulation 030104 developmental biology 030220 oncology & carcinogenesis Cancer research biology.protein Signal transduction medicine.drug |
| Zdroj: | Angewandte Chemie International Edition. 57:11629-11633 |
| ISSN: | 1521-3773 1433-7851 |
| Popis: | Exon 20 insertion (Ex20Ins) mutations are the third most prevalent epidermal growth factor receptor (EGFR) activating mutation and the most prevalent HER2 mutation in non-small cell lung cancer (NSCLC). Novel therapeutics for the patients with Ex20Ins mutations are urgently needed, due to their poor responses to the currently approved EGFR and HER2 inhibitors. Here we report the discovery of highly potent and broadly effective EGFR and HER2 Ex20Ins mutant inhibitors. The co-crystal structure of compound 1 b in complex with wild type EGFR clearly revealed an additional hydrophobic interaction of 4-fluorobenzene ring within a deep hydrophobic pocket, which has not been widely exploited in the development of EGFR and HER2 inhibitors. As compared with afatinib, compound 1 a exhibited superior inhibition of proliferation and signaling pathways in Ba/F3 cells harboring either EGFR or HER2 Ex20Ins mutations, and in the EGFR P772_H773insPNP patient-derived lung cancer cell line DFCI127. Our study identifies promising strategies for development of EGFR and HER2 Ex20Ins mutant inhibitors. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text