title: Systematic diversification of benzylidene heterocycles yields novel inhibitor scaffolds selective for Dyrk1A, Clk1 and CK2.
abstract: 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.
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
authors.forename: Marica
authors.initials: M
authors.lastname: Mariano
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2-3, D 66123 Saarbrücken, Germany.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany. Electronic address: ma.engel@mx.uni-saarland.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Engel
mesh_terms: D015107:4-Butyrolactone / Q000737:chemistry* / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000737:chemistry / Q000494:pharmacology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D015107:4-Butyrolactone; D001597:Benzylidene Compounds; D047390:Casein Kinase II; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C066780:Clk dual-specificity kinases
keywords: Alzheimer; Dyrk1A; Glioma; Multi-targeted inhibitor; PI3 kinase