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

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

Research output: Contribution to journalArticlepeer-review

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 (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-RA
Original languageEnglish
Pages (from-to)407-416
Number of pages10
JournalJournal of Medicinal Chemistry
DOIs
Publication statusPublished - Jan 2006

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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