title: Discovery and optimization of N-acyl and N-aroylpyrazolines as B-Raf kinase inhibitors.
abstract: A high throughput screen identified N-aroylpyrazoline 1 as a selective inhibitor of the V600E mutant of B-Raf kinase. Parallel synthesis of acyl, aroyl, and sulfonyl derivatives led to the identification of several potent inhibitors in both enzymatic and cellular (pERK) assays such as compound 42.
authors.affiliation: Millennium Pharmaceuticals Inc., 40 Landsdowne St., Cambridge MA 01239, United States. blackburn@mpi.com
authors.forename: Christopher
authors.initials: C
authors.lastname: Blackburn
authors.forename: Matthew O
authors.initials: MO
authors.lastname: Duffey
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Gould
authors.forename: Bheemashankar
authors.initials: B
authors.lastname: Kulkarni
authors.forename: Jane X
authors.initials: JX
authors.lastname: Liu
authors.forename: Saurabh
authors.initials: S
authors.lastname: Menon
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nagayoshi
authors.forename: Tricia J
authors.initials: TJ
authors.lastname: Vos
authors.forename: Juliet
authors.initials: J
authors.lastname: Williams
mesh_terms: D019943:Amino Acid Substitution; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011994:Recombinant Proteins; D048493:Proto-Oncogene Proteins B-raf