Pyridoimidazolones as Novel Potent Inhibitors of v-Raf Murine Sarcoma Viral Oncogene Homologue B1 (BRAF)
| Autor: | Florence I. Raynaud, Ion Niculescu-Duvaz, Catherine Gaulon, Douglas Hedley, Bart M. J. M. Suijkerbuijk, Caroline J. Springer, Ruth Kirk, Arnaud Nourry, Frank Friedlos, Javier Moreno-Farre, Richard Marais, Lesley Ogilvie, Dan Niculescu-Duvaz, Alfonso Zambon, Delphine Menard, Harmen P. Dijkstra, Adrian Liam Gill, Helen A. Manne, Richard D. Taylor, Lawrence Davies, Steven R. Whittaker |
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| Rok vydání: | 2009 |
| Předmět: |
Proto-Oncogene Proteins B-raf
endocrine system diseases Pyridines Transplantation Heterologous Mutant Melanoma Experimental Viral Oncogene Mice Nude Antineoplastic Agents In Vitro Techniques Serine Mice Structure-Activity Relationship Pharmacokinetics Cell Line Tumor Drug Discovery Animals Drug Screening Assays Antitumor Female Humans Imidazoles Microsomes Liver Mutation Neoplasm Transplantation Molecular Medicine Drug Discovery3003 Pharmaceutical Science Potency Threonine neoplasms Chemistry Kinase Methylation digestive system diseases Biochemistry Cancer research |
| Zdroj: | Journal of Medicinal Chemistry. 52:2255-2264 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm801509w |
| Popis: | BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50-70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanomolar potency for mutant BRAF (12 nM for compound 5i) and low micromolar cellular potency against a mutant BRAF melanoma cell line, WM266.4. The series benefits from very low metabolism, and pharmacokinetics (PK) that can be modulated by methylation of the NH groups of the imidazolone, resulting in compounds with fewer H-donors and a better PK profile. These compounds have great potential in the treatment of mutant BRAF melanomas. |
| Databáze: | OpenAIRE |
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