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Eur J Med Chem. 2016 Apr 13;112:209-216. doi: 10.1016/j.ejmech.2016.02.017. Epub 2016 Feb 9.

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

Author information

1
Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
2
Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2-3, D 66123 Saarbrücken, Germany.
3
Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany. Electronic address: ma.engel@mx.uni-saarland.de.

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.

KEYWORDS:

Alzheimer; Dyrk1A; Glioma; Multi-targeted inhibitor; PI3 kinase

PMID:
26896709
DOI:
10.1016/j.ejmech.2016.02.017
[Indexed for MEDLINE]

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