Development of a novel class of B-Raf(V600E)-selective inhibitors through virtual screening and hierarchical hit optimization
文献类型：期刊论文
| 作者 | Kong, Xiangqian1; Qin, Jie2; Li, Zeng1; Vultur, Adina2; Tong, Linjiang1; Feng, Enguang1; Rajan, Geena2; Liu, Shien1; Lu, Junyan1; Liang, Zhongjie1 |
| 刊名 | ORGANIC & BIOMOLECULAR CHEMISTRY
 |
| 出版日期 | 2012 |
| 卷号 | 10期号:36页码:7402-7417 |
| ISSN号 | 1477-0520 |
| DOI | 10.1039/c2ob26081f |
| 文献子类 | Article |
| 英文摘要 | 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 IC50 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 IC50 values with selectivity for B-Raf(V600E) in vitro and exclusive cytotoxicity against B-Raf(V600E) harboring cancer cells. |
| WOS关键词 | PROTEIN-LIGAND DOCKING ; BRAF V600E MUTATION ; B-RAF KINASE ; RAF/MEK/ERK PATHWAY ; GENETIC ALGORITHM ; SELECTIVE INHIBITORS ; METASTATIC MELANOMA ; SIGNALING PATHWAYS ; CLINICAL-TRIALS ; HYBRID APPROACH |
| 资助项目 | National Institutes of Health (NIH)[CA114046] ; State Key Program of Basic Research of China[2009CB918502] ; National Natural Science Foundation of China[20972174] ; National Natural Science Foundation of China[91029704] ; National Natural Science Foundation of China[21021063] ; National Natural Science Foundation of China[81025017] ; National S&T Major Projects[2012ZX09103-101-072] ; National High Technology Research and Development Program of China[2012AA020302] ; Chinese Academy of Sciences[XDA01040305] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000307790600020 |
| 出版者 | ROYAL SOC CHEMISTRY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278249]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药物发现与设计中心 |
| 通讯作者 | Liu, Hong |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA; 3.Soochow Univ, Ctr Syst Biol, Suzhou 215006, Jiangsu, Peoples R China |
| 推荐引用方式 GB/T 7714 | Kong, Xiangqian,Qin, Jie,Li, Zeng,et al. Development of a novel class of B-Raf(V600E)-selective inhibitors through virtual screening and hierarchical hit optimization[J]. ORGANIC & BIOMOLECULAR CHEMISTRY,2012,10(36):7402-7417. |
| APA | Kong, Xiangqian.,Qin, Jie.,Li, Zeng.,Vultur, Adina.,Tong, Linjiang.,...&Luo, Cheng.(2012).Development of a novel class of B-Raf(V600E)-selective inhibitors through virtual screening and hierarchical hit optimization.ORGANIC & BIOMOLECULAR CHEMISTRY,10(36),7402-7417. |
| MLA | Kong, Xiangqian,et al."Development of a novel class of B-Raf(V600E)-selective inhibitors through virtual screening and hierarchical hit optimization".ORGANIC & BIOMOLECULAR CHEMISTRY 10.36(2012):7402-7417. |
入库方式： OAI收割
来源：上海药物研究所
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