Novel inhibitors of B-RAF based on a disubstituted pyrazine scaffold. Generation of a nanomolar lead.

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Niculescu-Duvaz I, Roman E, Whittaker SR, Friedlos F, Kirk R, Scanlon IJ, Davies LC, Niculescu-Duvaz D, Marais R, Springer CJ

Novel inhibitors of B-RAF based on a disubstituted pyrazine scaffold. Generation of a nanomolar lead.

J Med Chem. 2006 Jan 12;49(1):407-16.

PubMed ID
16392826 [ View in PubMed
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Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
SorafenibSerine/threonine-protein kinase B-rafIC 50 (nM)46N/AN/ADetails
SorafenibSerine/threonine-protein kinase B-rafIC 50 (nM)6100N/AN/ADetails