A triazolotriazine-based dual GSK-3β/CK-1δ ligand as a potential neuroprotective agent presenting two different mechanisms of enzymatic inhibition

Sara Redenti, Irene Marcovih, Teresa De Vita, Conception Perez, Rita De Zorzi, Nicola Demitri, Daniel I Perez, Giovanni Bottegoni, Paola Bisignano, Maicol Bissaro, Stefano Moro, Ana Martinez, Paola Storici, Giampiero Spalluto, Andrea Cavalli, Stephanie Federico

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Glycogen synthase kinase 3β (GSK-3β) and casein kinase 1δ (CK-1δ) are emerging targets for the treatment of neuroinflammatory disorders, including Parkinson's disease. An inhibitor able to target these two kinases was developed by docking-based design. Compound 12, 3-(7-amino-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)-2-cyanoacrylamide, showed combined inhibitory activity against GSK-3β and CK-1δ [IC 50(GSK-3β)=0.17 μm; IC 50(CK-1δ)=0.68 μm]. In particular, classical ATP competition was observed against CK-1δ, and a co-crystal of compound 12 inside GSK-3β confirmed a covalent interaction between the cyanoacrylamide warhead and Cys199, which could help in the development of more potent covalent inhibitors of GSK-3β. Preliminary studies on in vitro models of Parkinson's disease revealed that compound 12 is not cytotoxic and shows neuroprotective activity. These results encourage further investigations to validate GSK-3β/CK-1δ inhibition as a possible new strategy to treat neuroinflammatory/degenerative diseases.

Original languageEnglish
Pages (from-to)310-314
Number of pages5
JournalChemMedChem
Volume14
Issue number3
Early online date12 Dec 2018
DOIs
Publication statusPublished - 5 Feb 2019

Keywords

  • casein kinase 1δ
  • glycogen synthase kinase 3β
  • neuroinflammation
  • Parkinson's disease
  • thia-Michael reaction

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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