Novel inhibitors of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) based on a 2,6-disubstituted pyrazine scaffold

Article abstract of DOI:10.1021/jm070776b

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.