Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring
| Autor: | Menard, Delphine, Niculescu Duvaz Ion, Dijkstra, Harmen P, I. Niculescu Duvaz, Dan, Suijkerbuijk, Bart M. J. M., Zambon, Alfonso, Nourry, Arnaud, Roman, Esteban, Davies, Lawrence, Marine, Friedlos, Frank, And, Helen A., Kirk, Ruth and, Gill, Adrian, Whittaker, Steven, Taylor, Richard D, Marais, Richard, Springer, Caroline |
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| Rok vydání: | 2009 |
| Předmět: |
Proto-Oncogene Proteins B-raf
MAPK/ERK pathway biology Pyridines Chemistry Stereochemistry Kinase Allosteric regulation Mutation Missense Antineoplastic Agents Ring (chemistry) Serine Inhibitory Concentration 50 Structure-Activity Relationship Phenols Mitogen-activated protein kinase Drug Discovery biology.protein Molecular Medicine Kinase activity Threonine Melanoma Allosteric Site |
| Zdroj: | Journal of Medicinal Chemistry. 52:3881-3891 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm900242c |
| Popis: | BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as a downstream effector of RAS, is a potential therapeutic target in melanoma. We have developed a series of small-molecule BRAF inhibitors based on a 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) as the hinge binding moiety and a number of substituted phenyl rings C that interact with the allosteric binding site. The introduction of various groups on the central phenyl ring B combined with appropriate A- and C-ring modifications afford very potent compounds that inhibit (V600E)BRAF kinase activity in vitro and oncogenic BRAF signaling in melanoma cells. Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC(50) of 1 nM for purified (V600E)BRAF and nanomolar activity in cells. |
| Databáze: | OpenAIRE |
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