Development of a novel class of B-RafV600E-selective inhibitors through virtual screening and hierarchical hit optimizationElectronic supplementary information (ESI) available. See DOI: 10.1039/c2ob26081f

• Main Authors: Kong, Xiangqian, Qin, Jie, Li, Zeng, Vultur, Adina, Tong, Linjiang, Feng, Enguang, Rajan, Geena, Liu, Shien, Lu, Junyan, Liang, Zhongjie, Zheng, Mingyue, Zhu, Weiliang, Jiang, Hualiang, Herlyn, Meenhard, Liu, Hong, Marmorstein, Ronen, Luo, Cheng
• Format: Journal Article
• Language: English
• Published: 22.08.2012
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c2ob26081f

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. Identification of B-Raf V600E selective inhibitors.