title: Development of a novel class of B-Raf(V600E)-selective inhibitors through virtual screening and hierarchical hit optimization.
abstract: Oncogenic mutations in critical nodes of cellular signaling pathways have been associated with tumorigenesis and progression. The B-Raf protein kinase, a key hub in the canonical MAPK signaling cascade, is mutated in a broad range of human cancers and especially in malignant melanoma. The most prevalent B-Raf(V600E) mutant exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, we describe the development of novel B-Raf(V600E) selective inhibitors via multi-step virtual screening and hierarchical hit optimization. Nine hit compounds with low micromolar IC(50) values were identified as B-Raf(V600E) inhibitors through virtual screening. Subsequent scaffold-based analogue searching and medicinal chemistry efforts significantly improved both the inhibitor potency and oncogene selectivity. In particular, compounds 22f and 22q possess nanomolar IC(50) values with selectivity for B-Raf(V600E)in vitro and exclusive cytotoxicity against B-Raf(V600E) harboring cancer cells.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Kong
authors.forename: Jie
authors.initials: J
authors.lastname: Qin
authors.forename: Zeng
authors.initials: Z
authors.lastname: Li
authors.forename: Adina
authors.initials: A
authors.lastname: Vultur
authors.forename: Linjiang
authors.initials: L
authors.lastname: Tong
authors.forename: Enguang
authors.initials: E
authors.lastname: Feng
authors.forename: Geena
authors.initials: G
authors.lastname: Rajan
authors.forename: Shien
authors.initials: S
authors.lastname: Liu
authors.forename: Junyan
authors.initials: J
authors.lastname: Lu
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Liang
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D006801:Humans; 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* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf