Discovery and optimization of covalent EGFR T790M/L858R mutant inhibitors
| Autor: | Maaike Emmelot, Dennis Demont, Edwin de Zwart, Allard Kaptein, Bas van de Kar, Saskia Verkaik, Tjeerd Barf, Niels Hoogenboom |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Clinical Biochemistry Mutant Pharmaceutical Science medicine.disease_cause Afatinib Biochemistry chemistry.chemical_compound T790M Structure-Activity Relationship Drug Discovery medicine Humans Epidermal growth factor receptor Molecular Biology Protein Kinase Inhibitors Mutation Acrylamides Aniline Compounds biology Dose-Response Relationship Drug Molecular Structure Organic Chemistry Wild type Rash respiratory tract diseases ErbB Receptors chemistry Covalent bond Cancer research biology.protein Molecular Medicine medicine.symptom Lead compound |
| Zdroj: | Bioorganicmedicinal chemistry letters. 52 |
| ISSN: | 1464-3405 |
| Popis: | Epidermal growth factor receptor (EGFR) inhibitors have clinical utility in the treatment of non-small cell lung cancer (NSCLC) patients. Despite encouraging clinical efficacy with these agents, many patients develop resistance due to sensitizing (or activating) mutations ultimately leading to disease progression. In the majority of the cases, this resistance is due to the T790M mutation and frequently coexisting L858R. In addition, EGFR wild type receptor inhibition can lead to on target related dose limiting toxicities such as rash and diarrhea. We describe herein the identification of a mutant selective lead compound 12, an irreversible covalent inhibitor of EGFR T790M/L858R resistance mutations with selectivity over the wild type form. Significant tumor growth inhibition in preclinical models was observed with this lead. |
| Databáze: | OpenAIRE |
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