Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring
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- 作者：Delphine Mnard ; Ion Niculescu-Duvaz ; Harmen P. Dijkstra ; Dan Niculescu-Duvaz ; Bart M. J. M. Suijkerbuijk ; Alfonso Zambon ; Arnaud Nourry ; Esteban Roman ; Lawrence Davies ; Helen A. Manne ; Frank Friedlos
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：July 9, 2009
- 年：2009
- 卷：52
- 期：13
- 页码：3881-3891
- 全文大小：316K
- 年卷期：v.52,no.13(July 9, 2009)
- ISSN：1520-4804
文摘
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 V600EBRAF 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 IC50 of 1 nM for purified V600EBRAF and nanomolar activity in cells.