Thienoquinolines as novel disruptors of the PKC?/RACK2 protein-protein interaction.

ABSTRACT: Ten protein kinase C (PKC) isozymes play divergent roles in signal transduction. Because of sequence similarities, it is particularly difficult to generate isozyme-selective small molecule inhibitors. In order to identify such a selective binder, we derived a pharmacophore model from the peptide EAVSLKPT, a fragment of PKC? that inhibits the interaction of PKC? and receptor for activated C-kinase 2 (RACK2). A database of 330?000 molecules was screened in silico, leading to the discovery of a series of thienoquinolines that disrupt the interaction of PKC? with RACK2 in vitro. The most active molecule, N-(3-acetylphenyl)-9-amino-2,3-dihydro-1,4-dioxino[2,3-g]thieno[2,3-b]quinoline-8-carboxamide (8), inhibited this interaction with a measured IC50 of 5.9 ?M and the phosphorylation of downstream target Elk-1 in HeLa cells with an IC50 of 11.2 ?M. Compound 8 interfered with MARCKS phosphorylation and TPA-induced translocation of PKC? (but not that of PKC?) from the cytosol to the membrane. The compound reduced the migration of HeLa cells into a gap, reduced invasion through a reconstituted basement membrane matrix, and inhibited angiogenesis in a chicken egg assay.

SUBMITTER: Rechfeld F 

PROVIDER: S-EPMC4001449 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature