Small-molecule inhibitors of ERK-mediated immediate early gene expression and proliferation of melanoma cells expressing mutated BRaf.

Abstract

Constitutive activation of the extracellular-signal-regulated kinases 1 and 2 (ERK1/2) are central to regulating the proliferation and survival of many cancer cells. The current inhibitors of ERK1/2 target ATP binding or the catalytic site and are therefore limited in their utility for elucidating the complex biological roles of ERK1/2 through its phosphorylation and regulation of over 100 substrate proteins. To overcome this limitation, a combination of computational and experimental methods was used to identify low-molecular-mass inhibitors that are intended to target ERK1/2 substrate-docking domains and selectively interfere with ERK1/2 regulation of substrate proteins. In the present study, we report the identification and characterization of compounds with a thienyl benzenesulfonate scaffold that were designed to inhibit ERK1/2 substrates containing an F-site or DEF (docking site for ERK, FXF) motif. Experimental evidence shows the compounds inhibit the expression of F-site containing immediate early genes (IEGs) of the Fos family, including c-Fos and Fra1, and transcriptional regulation of the activator protein-1 (AP-1) complex. Moreover, this class of compounds selectively induces apoptosis in melanoma cells containing mutated BRaf and constitutively active ERK1/2 signalling, including melanoma cells that are inherently resistant to clinically relevant kinase inhibitors. These findings represent the identification and initial characterization of a novel class of compounds that inhibit ERK1/2 signalling functions and their potential utility for elucidating ERK1/2 and other signalling events that control the growth and survival of cancer cells containing elevated ERK1/2 activity.

• Authors: Ramin Samadani, Jun Zhang, Amanda Brophy, Taiji Oashi, U Deva Priyakumar, E Prabhu Raman, Franz J St John, Kwan-Young Jung, Steven Fletcher, Edwin Pozharski, Alexander D MacKerell Jr, Paul Shapiro
• Journal: The Biochemical journal (Biochem J) Vol. 467 Issue 3 Pg. 425-38 (May 01 2015) ISSN: 1470-8728 [Electronic] England
• PMID: 25695333 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Ligands
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-fos
• Transcription Factor AP-1
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Computer Simulation
• Drug Design
• Drug Screening Assays, Antitumor
• Gene Expression (drug effects)
• Genes, Immediate-Early (drug effects)
• HeLa Cells
• Humans
• Jurkat Cells
• Ligands
• MAP Kinase Signaling System (drug effects, genetics)
• Melanoma (drug therapy, genetics, pathology)
• Models, Molecular
• Molecular Dynamics Simulation
• Mutation
• Phosphorylation
• Promoter Regions, Genetic (drug effects)
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Proto-Oncogene Proteins B-raf (genetics)
• Proto-Oncogene Proteins c-fos (chemistry, metabolism)
• Serum Response Element
• Transcription Factor AP-1 (genetics)