Novel Inhibitors of the v-raf Murine Sarcoma Viral Oncogene Homologue B1 (BRAF) Based on a 2,6-Disubstituted Pyrazine Scaffold.
作者
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.;
[摘要]：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 [I (R = BRAF inhibitor from a high-throughput screen of a library of 23000 compds. This compd. 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 II . In this paper, we describe the synthesis of a series of compds., e.g. I (R = 1-naphthalenyloxy, 4-pyridinyloxy, 5-quinolinyloxy, etc.), derived from II 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 biol. activity of the new inhibitors was assessed against mutant V600EBRAF in vitro. Several compds. were identified with IC50s of 300-500 nM for V600EBRAF; and all compds. that were assessed showed selectivity for V600EBRAF compared to CRAF by 5->86-fold.
