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Issue 36, 2012
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Development of a novel class of B-RafV600E-selective inhibitors through virtual screening and hierarchical hit optimization

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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-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 IC50 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 IC50 values with selectivity for B-RafV600Ein vitro and exclusive cytotoxicity against B-RafV600E harboring cancer cells.

Graphical abstract: Development of a novel class of B-RafV600E-selective inhibitors through virtual screening and hierarchical hit optimization

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Supplementary files

Article information


Submitted
05 Jun 2012
Accepted
10 Jul 2012
First published
13 Jul 2012

Org. Biomol. Chem., 2012,10, 7402-7417
Article type
Paper

Development of a novel class of B-RafV600E-selective inhibitors through virtual screening and hierarchical hit optimization

X. Kong, J. Qin, Z. Li, A. Vultur, L. Tong, E. Feng, G. Rajan, S. Liu, J. Lu, Z. Liang, M. Zheng, W. Zhu, H. Jiang, M. Herlyn, H. Liu, R. Marmorstein and C. Luo, Org. Biomol. Chem., 2012, 10, 7402
DOI: 10.1039/C2OB26081F

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