Probing a 3, 4′-bis-guanidinium diaryl derivative as an allosteric inhibitor of the Ras pathway. Issue 19 (1st October 2015)

• Record Type: Journal Article
• Authors: Diez-Cecilia, Elena; Carson, Robert; Kelly, Brendan; van Schaeybroeck, Sandra; Murray, James T.; Rozas, Isabel
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 19(2015)
• Page Start: 4287
• Page End: 4292
• Publication Date: 2015-10-01
• Subjects: CRC colorectal cancer -- PK protein kinase -- PKI protein kinase inhibitor -- FDA Federal Drug Agency -- HL-60 acute myeloid leukaemia cell line -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- IC50 half maximal inhibitory concentration -- RCSB Protein Data Bank Research Collaboratory for Structural Bioinformatics protein data bank -- MD molecular dynamics -- 4-Cl-3-CF3-Ph 4-chloro-3-trifluoromethylphenyl -- DFG-motif aspartic acid, phenylalanine, glycine motif -- FRET fluorescence resonance energy transfer -- pKaH minus logarithm of the acid constant of equilibrium for weak basic species; Non-ATP competitive inhibitor -- Ras pathway -- Anti-cancer drug; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.07.082
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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. Compound3, 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. Compound3 also potently inhibited ERK1/2 signalling, inhibited EGFR activation, as well as Src, STAT3 and AKT phosphorylation. Mechanistically, compound3 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.