title: 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.affiliation: *Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: Ramin
authors.initials: R
authors.lastname: Samadani
authors.affiliation: *Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: *Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: Amanda
authors.initials: A
authors.lastname: Brophy
authors.affiliation: *Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: Taiji
authors.initials: T
authors.lastname: Oashi
authors.affiliation: *Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: U Deva
authors.initials: UD
authors.lastname: Priyakumar
authors.affiliation: *Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: E Prabhu
authors.initials: EP
authors.lastname: Raman
authors.affiliation: *Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: Franz J
authors.initials: FJ
authors.lastname: St John
authors.affiliation: *Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: Kwan-Young
authors.initials: KY
authors.lastname: Jung
authors.affiliation: *Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
authors.affiliation: *Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: Edwin
authors.initials: E
authors.lastname: Pozharski
authors.affiliation: *Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
authors.affiliation: *Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: Paul
authors.initials: P
authors.lastname: Shapiro
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003198:Computer Simulation; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000737:chemistry / Q000378:metabolism; D027602:Serum Response Element; D018808:Transcription Factor AP-1 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf