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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.

SUBMITTER: Kong X 

PROVIDER: S-EPMC3427755 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Development of a novel class of B-Raf(V600E)-selective inhibitors through virtual screening and hierarchical hit optimization.

Kong Xiangqian X   Qin Jie J   Li Zeng Z   Vultur Adina A   Tong Linjiang L   Feng Enguang E   Rajan Geena G   Liu Shien S   Lu Junyan J   Liang Zhongjie Z   Zheng Mingyue M   Zhu Weiliang W   Jiang Hualiang H   Herlyn Meenhard M   Liu Hong H   Marmorstein Ronen R   Luo Cheng C  

Organic & biomolecular chemistry 20120901 36


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 th  ...[more]

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