Highly potent and selective 3-N-methylquinazoline-4(3H)-one based inhibitors of B-RafV600E kinase
| Autor: | Victoria Dinkel, Jonas Grina, David A. Moreno, Simon Mathieu, Joshua D. Hansen, Kevin Rasor, Gregg Hastings, Walter C. Voegtli, Guy Vigers, Sumeet Rana, Joachim Rudolph, Susan L. Gloor, Ellen R. Laird, Li Ren, Steve Wenglowsky, Brandon S. Willis, Hillary L. Sturgis |
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| Rok vydání: | 2014 |
| Předmět: |
Proto-Oncogene Proteins B-raf
Stereochemistry Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Crystallography X-Ray Biochemistry Inhibitory Concentration 50 chemistry.chemical_compound Pharmacokinetics Amide Drug Discovery Animals Humans Potency Protein Kinase Inhibitors Molecular Biology chemistry.chemical_classification Molecular Structure Kinase Drug discovery Aryl Organic Chemistry Xenograft Model Antitumor Assays Tumor Burden Sulfonamide Enzyme Activation chemistry Drug Design Quinazolines Molecular Medicine Selectivity |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 24:1923-1927 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2014.03.007 |
| Popis: | Herein we describe the design of a novel series of ATP competitive B-Raf inhibitors via structure-based methods. These 3-N-methylquinazoline-4(3H)-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 16, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. Our work also demonstrates that by replacing an aryl amide with an aryl sulfonamide, a multikinase inhibitor such as AZ-628, can be converted to a selective B-Raf inhibitor, a finding that should have broad application in kinase drug discovery. |
| Databáze: | OpenAIRE |
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