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Discovery of N -aryl- N ′-pyrimidin-4-yl ureas as irreversible L858R/T790M mutant selective epidermal growth factor receptor inhibitors
- Source :
- Bioorganic & Medicinal Chemistry Letters. 28:1257-1261
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- A novel series of N-aryl-N′-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the EGFR L858R/T790M. The most representative compound 28 showed high activity against EGFR L858R/T790M kinase (IC50 = 4 nM) and 22-fold selectivity against wild type EGFR. Moreover, compound 28 potently inhibited EGFR L858R/T790M phosphorylation (IC50 = 41 nM) and cellular proliferation (IC50 = 37 nM) in the H1975 cell line, while being significantly less toxic to A431 cells. Further, compound 28 exhibited a great selectivity in a mini-panel of kinases.
- Subjects :
- 0301 basic medicine
Clinical Biochemistry
Mutant
Pharmaceutical Science
Antineoplastic Agents
Biochemistry
Structure-Activity Relationship
03 medical and health sciences
T790M
0302 clinical medicine
Cell Line, Tumor
Drug Discovery
Humans
Urea
Phosphorylation
Protein Kinase Inhibitors
Molecular Biology
Cell Proliferation
Dose-Response Relationship, Drug
Molecular Structure
Chemistry
Kinase
Organic Chemistry
Wild type
Molecular biology
respiratory tract diseases
ErbB Receptors
Molecular Docking Simulation
030104 developmental biology
Cell culture
030220 oncology & carcinogenesis
Mutation
Molecular Medicine
Drug Screening Assays, Antitumor
Selectivity
A431 cells
Subjects
Details
- ISSN :
- 0960894X
- Volume :
- 28
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Accession number :
- edsair.doi.dedup.....579019b01706e9955df71ae583bded59