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

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

  • Bioorg Med Chem Lett. 2015 Oct 1;25(19):4287-92. doi: 10.1016/j.bmcl.2015.07.082.
Elena Diez-Cecilia 1,  Robert Carson 2,  Brendan Kelly 1,  Sandra van Schaeybroeck 2,  James T Murray 3,  Isabel Rozas 4
Affiliations

Affiliations

  • 1 School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
  • 2 Drug Resistance Group, Centre for Cancer Research and Cell Biology, 97 Lisburn Road, Belfast BT9 7BL, UK.
  • 3 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
  • 4 School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland. Electronic address: rozasi@tcd.ie.
PMID: 26318998 DOI: 10.1016/j.bmcl.2015.07.082
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.

Keywords

Anti-cancer drug; Non-ATP competitive inhibitor; Ras pathway.

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