基于二取代吡嗪骨架的新型B-RAF抑制剂。纳摩尔级先导化合物的产生。
Novel inhibitors of B-RAF based on a disubstituted pyrazine scaffold. Generation of a nanomolar lead.
作者信息
Niculescu-Duvaz Ion, Roman Esteban, Whittaker Steven R, Friedlos Frank, Kirk Ruth, Scanlon Ian J, Davies Lawrence C, Niculescu-Duvaz Dan, Marais Richard, Springer Caroline J
机构信息
Cancer Research UK Centre for Cancer Therapeutics at the Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
出版信息
J Med Chem. 2006 Jan 12;49(1):407-16. doi: 10.1021/jm050983g.
B-RAF, a serine/threonine kinase, plays an important role in the development of certain classes of cancer, especially melanoma. As a result of high-throughput screening of a 23,000 compound library, 2-(3,4,5-trimethoxyphenylamino)-6-(3-acetamidophenyl)pyrazine, 1, was identified as a low micromolar (IC(50) = 3.5 microM) B-RAF inhibitor. This compound was chosen as the starting point of a program aimed at producing potent inhibitors of B-RAF. We have synthesized a series of 40 novel compounds, which involved extensive modifications to the 2-(3,4,5-trimethoxyphenylamino) moiety (ring A) of 1. Their biological profiles against isolated B-RAF and mutated B-RAF in a cellular assay have been determined. These efforts led to the identification of two compounds exhibiting activities lower than 800 nM against B-RAF.
B-RAF是一种丝氨酸/苏氨酸激酶，在某些类型癌症尤其是黑色素瘤的发展过程中发挥着重要作用。通过对一个包含23,000种化合物的文库进行高通量筛选，2-(3,4,5-三甲氧基苯基氨基)-6-(3-乙酰氨基苯基)吡嗪（1）被鉴定为一种低微摩尔浓度（IC(50)=3.5微摩尔）的B-RAF抑制剂。该化合物被选作旨在生产强效B-RAF抑制剂的项目的起始点。我们合成了一系列40种新型化合物，其中对1的2-(3,4,5-三甲氧基苯基氨基)部分（A环）进行了广泛修饰。已测定了它们在细胞试验中针对分离的B-RAF和突变型B-RAF的生物学特性。这些研究工作导致鉴定出两种对B-RAF活性低于800纳摩尔的化合物。
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