title: Probing a 3,4'-bis-guanidinium diaryl derivative as an allosteric inhibitor of the Ras pathway.
abstract: Mutations in the Ras-pathway occur in 40-45% of colorectal cancer patients and these are refractory to treatment with anti-EGFR-targeted therapies. With this in mind, we have studied novel guanidinium-based compounds with demonstrated ability to inhibit protein kinases. We have performed docking studies with several proteins involved in the Ras-pathway and evaluated 3,4'-bis-guanidinium derivatives as inhibitors of B-Raf. Compound 3, the most potent in this series, demonstrated strong cytotoxicity in (WT)B-Raf colorectal cancer cells and also cells with (V600E)B-Raf mutations. Cell death was induced by apoptosis, detected by cleavage of PARP. Compound 3 also potently inhibited ERK1/2 signalling, inhibited EGFR activation, as well as Src, STAT3 and AKT phosphorylation. Mechanistically, compound 3 did not inhibit ATP binding to B-Raf, but direct assay of B-Raf activity was inhibited in vitro. Summarizing, we have identified a novel B-Raf type-III inhibitor that exhibits potent cellular cytotoxicity.
authors: School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
authors: Elena
authors: E
authors: Diez-Cecilia
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors: Robert
authors: R
authors: Carson
authors: School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
authors: Brendan
authors: B
authors: Kelly
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors: Sandra
authors: S
authors: van Schaeybroeck
authors: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
authors: James T
authors: JT
authors: Murray
authors: School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland. Electronic address: rozasi@tcd.ie.
authors: Isabel
authors: I
authors: Rozas
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019791:Guanidine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D018631:ras Proteins; D019791:Guanidine
keywords: Anti-cancer drug; Non-ATP competitive inhibitor; Ras pathway