Systematic diversification of benzylidene heterocycles yields novel inhibitor scaffolds selective for Dyrk1A, Clk1 and CK2

• Published in: European journal of medicinal chemistry Vol. 112; pp. 209 - 216
• Main Authors: Mariano, Marica, Hartmann, Rolf W., Engel, Matthias
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 13.04.2016; Elsevier
• Subjects: 4-Butyrolactone - chemistry; 4-Butyrolactone - pharmacology; Alzheimer; Benzylidene Compounds - chemistry; Benzylidene Compounds - pharmacology; Casein Kinase II - antagonists & inhibitors; Casein Kinase II - metabolism; Chemistry, Medicinal; Drug Design; Dyrk Kinases; Dyrk1A; Glioma; HEK293 Cells; Humans; Life Sciences & Biomedicine; Models, Molecular; Multi-targeted inhibitor; Pharmacology & Pharmacy; PI3 kinase; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Science & Technology; Multi-targeted inhibitor; Glioma; PI3 kinase; Alzheimer; Dyrk1A; KINASE DYRK1A; ALZHEIMERS-DISEASE; DUAL-SPECIFICITY; PROTEIN-KINASES; TAU EXON 10; IN-VITRO; DOWN-SYNDROME; GENE-EXPRESSION; SYNDROME CRITICAL REGION; LEUCETTAMINE B
• DOI: 10.1016/j.ejmech.2016.02.017
• ISSN: 0223-5234

The dual-specificity tyrosine-regulated kinase 1A (Dyrk1A) has gathered much interest as a pharmacological target in Alzheimer's disease (AD), but it plays a role in malignant brain tumors as well. As both diseases are multi-factorial, further protein kinases, such as Clk1 and CK2, were proposed to contribute to the pathogenesis. We designed a new class of α-benzylidene–γ-butyrolactone inhibitors that showed low micromolar potencies against Dyrk1A and/or Clk1 and a good selectivity profile among the most frequently reported off-target kinases. A systematic replacement of the heterocyclic moiety gave access to further inhibitor classes with interesting selectivity profiles, demonstrating that the benzylidene heterocycles provide a versatile tool box for developing inhibitors of the CMGC kinase family members Dyr1A/1B, Clk1/4 and CK2. Efficacy for the inhibition of Dyrk1A–mediated tau phosphorylation was demonstrated in a cell-based assay. Multi-targeted but not non-specific kinase inhibitors were also obtained, that co-inhibited the lipid kinases PI3Kα/γ. These compounds were shown to inhibit the proliferation of U87MG cells in the low micromolar range. Based on the molecular properties, the inhibitors described here hold promise for CNS activity. [Display omitted] •A new α-benzylidene–γ-butyrolactone scaffold was designed and systematically diversified.•Several scaffolds showing selectivity for Dyrk1A, Clk1 and CK2 were identified, with IC50s from the low µM to the nM range.•Multi-targeted kinase inhibitors were also obtained, that co-inhibited the lipid kinases PI3Kα/γ.•Compounds possessing different scaffolds inhibited tau phosphorylation in intact cells.