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

Bioorganic & Medicinal Chemistry Letters
Elena Diez-CeciliaIsabel Rozas

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.

References

Jan 2, 2003·Nature Reviews. Cancer·Julian Downward
Mar 24, 2004·Cell·Paul T C WanUNKNOWN Cancer Genome Project
Feb 12, 2009·Current Opinion in Cell Biology·Sandra W Cowan-JacobDoriano Fabbro
Oct 26, 2012·Anti-cancer Agents in Medicinal Chemistry·Javier BlancChristel Menet

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