title: Structure-based de novo design and biochemical evaluation of novel BRAF kinase inhibitors.
abstract: VRAF murine sarcoma viral oncogene homologue B1 (BRAF) kinase has been considered to be a promising therapeutic target for various human cancers. We have been able to identify 24 novel BRAF kinase inhibitors with K(d) values ranging from 0.4 to 10μM utilizing a structure-based de novo design method with the two known inhibitor scaffolds. Because these discovered inhibitors were also screened for having desirable physicochemical properties as a drug candidate, they deserve consideration for further investigation as anticancer agents. Structural features relevant to the stabilization of the newly identified inhibitors in the ATP-binding site of BRAF are discussed in detail.
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-Dong, Kwangjin-Ku, Seoul 143-747, Republic of Korea.
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.forename: Yujeong
authors.initials: Y
authors.lastname: Jeong
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Hong
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; 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*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf