Small Molecule Inhibitors of ERK-mediated Immediate Early Gene Expression and Proliferation of Melanoma Cells Expressing Mutated BRaf

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 one hundred substrate proteins. To overcome this limitation, a combination of computational and experimental methods was used to identify small molecular weight inhibitors that are intended to target ERK1/2-substrate docking domains and selectively interfere with ERK1/2 regulation of substrate proteins. Here 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 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 signaling, 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 inhi...

Source: BJ Signal - February 19, 2015 Category: Biochemistry Authors: R Samadani, J Zhang, A Brophy, T Oashi, U Deva Priyakumar, E Prabhu Raman, F J. St. John, K Jung, S Fletcher, E Pozharski, A D MacKerell, P S Shapiro Tags: BJ ChemBio Source Type: research