Hydroxybenzothiophene Ketones Are Efficient Pre-mRNA Splicing Modulators Due to Dual Inhibition of Dyrk1A and Clk1/4.

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.

First selective dual inhibitors of tau phosphorylation and Beta-amyloid aggregation, two major pathogenic mechanisms in Alzheimer's disease.

In Alzheimer's disease (AD), multiple factors account for the accumulation of neurocellular changes, which may begin several years before symptoms appear. The most important pathogenic brain changes that are contributing to the development of AD are the formation of the cytotoxic ß-amyloid aggregates and of the neurofibrillary tangles, which originate from amyloid-ß peptides and hyperphosphorylated tau protein, respectively. New therapeutic agents that target both major pathogenic mechanisms may be particularly efficient. In this study, we introduce bis(hydroxyphenyl)-substituted thiophenes as a novel class of selective, dual inhibitors of the tau kinase Dyrk1A and of the amyloid-ß aggregation.

6-Hydroxybenzothiophene ketones: potent inhibitors of 17ß-hydroxysteroid dehydrogenase type†1 (17ß-HSD1) owing to favorable molecule geometry and conformational preorganization.

The inhibition of 17ß-hydroxysteroid dehydrogenase type 1 (17ß-HSD1), which catalyzes the conversion of estrone into the potent estrogen receptor agonist estradiol (E2), is discussed as a novel therapeutic approach for the treatment of estrogen-dependent diseases. Because the reduction of E2 would be basically limited to the target tissues, this approach is expected to cause fewer side effects than the currently employed antihormonal therapies. Recently, we reported on 6-hydroxybenzothiazole ketones as a new class of 17ß-HSD1 inhibitors with a notable activity/selectivity profile. In an attempt to further optimize these parameters, we modified the benzothiazole core by a systematic bioisosteric replacement. Thus, we were able to identify a new 6-hydroxybenzothiophene derivative that displayed stronger inhibition of 17ß-HSD1 (IC50 =13 nM) and that was also more selective than a benzothiazole analog. Using ab initio calculations, we found that the higher potency of the 6-hydroxybenzothiophene derivative was probably due to more favorable conformational preorganization of the scaffold for binding to the enzyme.