title: Identification of BRAF inhibitors through in silico screening.
abstract: The BRAF protein kinase, a molecule in the RAS-RAF-MEK-ERK signaling pathway, is mutated to harbor elevated kinase activity in approximately 7% of human cancers, which makes it an important therapeutic target for inhibition. Several BRAF protein-kinase inhibitors have been developed through high-throughout screening in vitro; however, many of these compounds suffer from a lack of suitable kinase specificity and other chemotherapeutic properties. In silico screening has evolved as a powerful complimentary approach to protein-kinase inhibitor identification. Here we describe an in silico screen for BRAF inhibitors that leads to the identification of a series of purine-2,6-dione analogues with IC50 values in the single-digit micromolar range and with significant selectivity for BRAF over other representative protein kinases. The binding modes of these inhibitors to BRAF are analyzed through molecular docking to derive structure-activity relationships and to assist in the future development of more potent and more specific BRAF inhibitors.
authors.affiliation: The Wistar Institute, University of Pennsylvania, Philadelphia, PA, 19104 USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.affiliation: The Wistar Institute, University of Pennsylvania, Philadelphia, PA, 19104 USA.|Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104 USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Xie
authors.affiliation: The Wistar Institute, University of Pennsylvania, Philadelphia, PA, 19104 USA.|Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104 USA.
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D003001:Cloning, Molecular; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D012680:Sensitivity and Specificity; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
references.citation: Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6388S-92S
references.pmid: 15448036
references.citation: Proteins. 1998 Oct 1;33(1):74-87
references.pmid: 9741846
references.citation: J Chem Inf Model. 2005 Jan-Feb;45(1):177-82
references.pmid: 15667143
references.citation: Cancer Res. 2006 Dec 1;66(23):11100-5
references.pmid: 17145850
references.citation: Cancer Res. 2004 Oct 1;64(19):7099-109
references.pmid: 15466206
references.citation: J Mol Recognit. 1996 Jan-Feb;9(1):1-5
references.pmid: 8723313
references.citation: Mol Cancer Ther. 2005 Apr;4(4):677-85
references.pmid: 15827342
references.citation: J Med Chem. 2003 Jun 19;46(13):2656-62
references.pmid: 12801229
references.citation: Cancer Cell. 2004 Oct;6(4):313-9
references.pmid: 15488754
references.citation: J Comput Aided Mol Des. 2002 Dec;16(12):883-902
references.pmid: 12825621
references.citation: J Med Chem. 2003 Jun 5;46(12):2287-303
references.pmid: 12773034
references.citation: Proc Natl Acad Sci U S A. 2007 May 1;104(18):7391-6
references.pmid: 17463090
references.citation: Cell. 2004 Mar 19;116(6):855-67
references.pmid: 15035987
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3041-6
references.pmid: 18287029