ArticleOrganic & biomolecular chemistry2012
Development of a novel class of B-Raf(V600E)-selective inhibitors through virtual screening and hierarchical hit optimization.
Article in Organic & biomolecular chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 22 citations in OpenAlex.
- Computational Approaches: A New Frontier in Cancer Research.Combinatorial chemistry & high throughput screening · 2024Review
- Design and synthesis of novel thiobarbituric acid derivatives targeting both wild-type and BRAF-mutated melanoma cells.European journal of medicinal chemistry · 2018Article
- Integrating docking scores and key interaction profiles to improve the accuracy of molecular docking: towards novel B-RafMedChemComm · 2017Article
- In silico identification of novel kinase inhibitors by targeting B-Raf(v660e) from natural products database.Journal of molecular modeling · 2015Article
- Insight into molecular dynamics simulation of BRAF(V600E) and potent novel inhibitors for malignant melanoma.International journal of nanomedicine · 2015Article
- Hierarchical virtual screening approaches in small molecule drug discovery.Methods (San Diego, Calif.) · 2015Review
- Identification and synthesis of N-(thiophen-2-yl) benzamide derivatives as BRAF(V600E) inhibitors.Bioorganic & medicinal chemistry letters · 2013Article
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Authors and funding
17 authors at 3 institutions in 2 countries.
Funding
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.
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