1400564-00-2Relevant academic research and scientific papers
Development of a novel class of B-RafV600E-selective inhibitors through virtual screening and hierarchical hit optimization
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
, p. 7402 - 7417 (2012/10/08)
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-RafV600E 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-RafV600E selective inhibitors via multi-step virtual screening and hierarchical hit optimization. Nine hit compounds with low micromolar IC 50 values were identified as B-RafV600E 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-RafV600Ein vitro and exclusive cytotoxicity against B-RafV600E harboring cancer cells.
