title: Novel inhibitors of B-RAF based on a disubstituted pyrazine scaffold. Generation of a nanomolar lead.
abstract: B-RAF, a serine/threonine kinase, plays an important role in the development of certain classes of cancer, especially melanoma. As a result of high-throughput screening of a 23,000 compound library, 2-(3,4,5-trimethoxyphenylamino)-6-(3-acetamidophenyl)pyrazine, 1, was identified as a low micromolar (IC(50) = 3.5 microM) B-RAF inhibitor. This compound was chosen as the starting point of a program aimed at producing potent inhibitors of B-RAF. We have synthesized a series of 40 novel compounds, which involved extensive modifications to the 2-(3,4,5-trimethoxyphenylamino) moiety (ring A) of 1. Their biological profiles against isolated B-RAF and mutated B-RAF in a cellular assay have been determined. These efforts led to the identification of two compounds exhibiting activities lower than 800 nM against B-RAF.
authors.affiliation: Cancer Research UK Centre for Cancer Therapeutics at the Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
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: D000083:Acetanilides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C507823:2-(3,4,5-trimethoxyphenylamino)-6-(3-acetamidophenyl)pyrazine; D000083:Acetanilides; D011719:Pyrazines; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf