Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring
Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring
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DOI：
10.1021/jm900242c
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发表时间：
2009-07-09
影响因子：
7.3
通讯作者：
Springer, Caroline J.
中科院分区：
文献类型：
--
作者：
Menard, Delphine;Niculescu-Duvaz, Ion;Springer, Caroline J.
BRAF是一种丝氨酸/苏氨酸特异性蛋白激酶，是MAPK通路的一部分，是RAS的下游效应物，是黑色素瘤的潜在治疗靶点。我们已经开发了一系列基于1h -咪唑[4,5-b]吡啶-2(3H)- 1支架（环a）作为铰链结合部分和一些取代苯基环C与变构结合位点相互作用的小分子BRAF抑制剂。在中心苯基环B上引入各种基团，并结合适当的A环和c环修饰，可以提供非常有效的化合物，在体外抑制（V600E）BRAF激酶活性和黑色素瘤细胞中的致癌BRAF信号传导。在3-氟基、萘基或3-硫甲基的中心苯基环上取代可提高活性，生成纯化（V600E）BRAF的IC50为1 nM的化合物，并在细胞中具有纳摩尔活性。
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 oncogqnic 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 (V600E)BRAF and nanomolar activity in cells.