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

Research output: Contribution to journalArticle

Authors

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

Colleges, School and Institutes

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.

Bibliographic note

S. Redenti, I. Marcovich, T. De Vita, C. Pérez, R. De Zorzi, N. Demitri, D. I. Perez, G. Bottegoni, P. Bisignano, M. Bissaro, S. Moro, A. Martinez, P. Storici, G. Spalluto, A. Cavalli, S. Federico, ChemMedChem 2019, 14, 310.

Details

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

Keywords

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