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

European Journal of Medicinal Chemistry
Marica MarianoMatthias Engel

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 promis...Continue Reading

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Citations

Sep 28, 2016·European Journal of Medicinal Chemistry·Christophe LabrièreCatherine Guillou
Jun 1, 2017·Journal of Medicinal Chemistry·Ahmed K ElHadyMatthias Engel
Feb 3, 2021·Journal of Medicinal Chemistry·Aurélien BeatoRomain Haudecoeur
Mar 7, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ahmed K ElHadyMatthias Engel

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