title: Hydroxybenzothiophene Ketones Are Efficient Pre-mRNA Splicing Modulators Due to Dual Inhibition of Dyrk1A and Clk1/4.
abstract: Dysregulated usage of pre-mRNA splicing sites contributes to the progression of cancer, neurodegenerative diseases, and viral infections. Serine/arginine-rich (SR) proteins play major roles in the splice site recognition and are largely regulated by phosphorylation. This provides an option for the pharmacological correction of aberrant splicing by inhibiting the relevant kinases. Cdc2-like kinases (Clks) and dual specificity tyrosine phosphorylation-regulated kinases (Dyrks) were both reported to phosphorylate numerous SR proteins in vitro and in vivo. In this study, we describe the discovery of new selective dual Clk/Dyrk1A/1B inhibitors, which are able to modulate alternative pre-mRNA splicing of model gene transcripts in cells with submicromolar potencies. The optimization process yielded a dual Clk and Dyrk inhibitor with exceptionally high ligand efficiency. Our results suggested that dual inhibition of both Clk1 and Dyrk1A increased the efficacy of pre-mRNA splicing modulation.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University , Campus C2.3, D-66123 Saarbrücken, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schmitt
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University , Campus C2.3, D-66123 Saarbrücken, Germany.
authors.forename: Parisa
authors.initials: P
authors.lastname: Miralinaghi
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University , Campus C2.3, D-66123 Saarbrücken, Germany.
authors.forename: Marica
authors.initials: M
authors.lastname: Mariano
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University , Campus C2.3, D-66123 Saarbrücken, Germany ; Department of Drug Design and Optimization, Helmholtz-Institut für Pharmazeutische Forschung Saarland , Campus C2.3, D-66123 Saarbrücken, Germany.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University , Campus C2.3, D-66123 Saarbrücken, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Engel
keywords: Dual kinase inhibitor; alternative splicing modifiers; cdc2-like kinases; dual specificity tyrosine (Y) phosphorylation regulated kinases