Probing a 3,4'-bis-guanidinium diaryl derivative as an allosteric inhibitor of the Ras pathway

Elena Diez-Cecilia , Robbie Carson, Brendan Kelly, Sandra Van Schaeybroeck, James T. Murray, Isabel Rozas

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


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 stud- ies with several proteins involved in the Ras-pathway and evaluated 3,40-bis-guanidinium derivatives as inhibitors of B-Raf. Compound 3, the most potent in this series, demonstrated strong cytotoxicity in WTB-Raf colorectal cancer cells and also cells with V600EB-Raf mutations. Cell death was induced by apop- tosis, 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
Original languageEnglish
Pages (from-to)4287-4292
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Issue number19
Early online date18 Aug 2015
Publication statusPublished - 01 Oct 2015


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