title: Novel inhibitors of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) based on a 2,6-disubstituted pyrazine scaffold.
abstract: 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 microM) 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 (V600E)BRAF. 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 (V600E)BRAF compared to CRAF. The biological activity of the new inhibitors was assessed against mutant (V600E)BRAF in vitro. Several compounds were identified with IC 50s of 300-500 nM for (V600E)BRAF, and all compounds that were assessed showed selectivity for (V600E)BRAF compared to CRAF by 5-->86-fold.
authors.affiliation: The Institute of Cancer Research, Cancer Research UK Centre for Cancer Therapeutics, Sutton, Surrey, UK.
authors.forename: Ion
authors.initials: I
authors.lastname: Niculescu-Duvaz
authors.forename: Esteban
authors.initials: E
authors.lastname: Roman
authors.forename: Steven R
authors.initials: SR
authors.lastname: Whittaker
authors.forename: Frank
authors.initials: F
authors.lastname: Friedlos
authors.forename: Ruth
authors.initials: R
authors.lastname: Kirk
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Scanlon
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Davies
authors.forename: Dan
authors.initials: D
authors.lastname: Niculescu-Duvaz
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Springer
mesh_terms: D016208:Databases, Factual; D006801:Humans; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000737:chemistry; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D011719:Pyrazines; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf