894416-87-6Relevant articles and documents
Novel inhibitors of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) based on a 2,6-disubstituted pyrazine scaffold
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.
experimental part, p. 3261 - 3274 (2009/04/06)
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 (IC 50 = 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.
