Portal de Periódicos da CAPES

Novel Inhibitors of B-RAF Based on a Disubstituted Pyrazine Scaffold. Generation of a Nanomolar Lead

2005; American Chemical Society; Volume: 49; Issue: 1 Linguagem: Inglês

10.1021/jm050983g

1520-4804

Ion Niculescu‐Duvaz, Esteban Román, Steven R. Whittaker, Frank Friedlos, Richard Kirk, Ian Scanlon, Lawrence Davies, Dan Niculescu‐Duvaz, Richard Marais, Caroline J. Springer,

Computational Drug Discovery Methods

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 (IC50 = 3.5 μM) 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.