title: Identification of a novel family of BRAF(V600E) inhibitors.
abstract: The BRAF oncoprotein is mutated in about half of malignant melanomas and other cancers, and a kinase activating single valine to glutamate substitution at residue 600 (BRAF(V600E)) accounts for over 90% of BRAF-mediated cancers. Several BRAF(V600E) inhibitors have been developed, although they harbor some liabilities, thus motivating the development of other BRAF(V600E) inhibitor options. We report here the use of an ELISA based high-throughput screen to identify a family of related quinolol/naphthol compounds that preferentially inhibit BRAF(V600E) over BRAF(WT) and other kinases. We also report the X-ray crystal structure of a BRAF/quinolol complex revealing the mode of inhibition, employ structure-based medicinal chemistry efforts to prepare naphthol analogues that inhibit BRAF(V600E) in vitro with IC(50) values in the 80-200 nM range under saturating ATP concentrations, and demonstrate that these compounds inhibit MAPK signaling in melanoma cells. Prospects for improving the potency and selectivity of these inhibitors are discussed.
authors.affiliation: The Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Qin
authors.forename: Peng
authors.initials: P
authors.lastname: Xie
authors.forename: Christian
authors.initials: C
authors.lastname: Ventocilla
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Zhou
authors.forename: Adina
authors.initials: A
authors.lastname: Vultur
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Winkler
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004797:Enzyme-Linked Immunosorbent Assay; D057166:High-Throughput Screening Assays; D006801:Humans; D006873:Hydroquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008545:Melanoma; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D009284:Naphthols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D006873:Hydroquinones; D009284:Naphthols; D048493:Proto-Oncogene Proteins B-raf