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Novel Inhibitors of the v-raf Murine Sarcoma Viral Oncogene Homologue B1 (BRAF) Based on a 2,6-Disubstituted Pyrazine Scaffold

2008; American Chemical Society; Volume: 51; Issue: 11 Linguagem: Inglês

10.1021/jm070776b

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,

Protein Degradation and Inhibitors

BRAF, a serine/threonine kinase, plays a key role in the development of certain types of cancer, particularly melanoma. 2-(3,4,5-Trimethoxyphenylamino)-6-(3-acetamidophenyl)-pyrazine, 1, was identified as a low micromolar (IC50 = 3.5 µM) BRAF inhibitor from a high-throughput screen of a library of 23000 compounds. This compound was chosen as the starting point of a program aimed at developing inhibitors of mutant V600EBRAF. We have already reported on the optimization of the trimethoxyphenylamino moiety of 1. In this paper, we describe the synthesis of a series of compounds derived from 1 with the purpose of optimization of the pyrazine central core and the phenylacetamido moiety in order to increase the potency against V600EBRAF compared to CRAF. The biological activity of the new inhibitors was assessed against mutant V600EBRAF in vitro. Several compounds were identified with IC50s of 300−500 nM for V600EBRAF, and all compounds that were assessed showed selectivity for V600EBRAF compared to CRAF by 5−>86-fold.