2. Academic Validation
  3. 7-Amino-[1,2,4]triazolo[1,5-a][1,3,5]triazines as CK1δ inhibitors: Exploring substitutions at the 2 and 5-positions

7-Amino-[1,2,4]triazolo[1,5-a][1,3,5]triazines as CK1δ inhibitors: Exploring substitutions at the 2 and 5-positions

  • Bioorg Chem. 2024 Jul 17:151:107659. doi: 10.1016/j.bioorg.2024.107659.
Ilenia Grieco 1,  Davide Bassani 2,  Letizia Trevisan 3,  Veronica Salmaso 4,  Eleonora Cescon 5,  Filippo Prencipe 6,  Tatiana Da Ros 7,  Loreto Martinez-Gonzalez 8,  Ana Martinez 9,  Giampiero Spalluto 10,  Stefano Moro 11,  Stephanie Federico 12
Affiliations

Affiliations

  • 1 Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy. Electronic address: ilenia.grieco@phd.units.it.
  • 2 Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131 Padova, Italy. Electronic address: davide.bassani.1@phd.unipd.it.
  • 3 Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy. Electronic address: letizia.trevisan@phd.units.it.
  • 4 Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131 Padova, Italy. Electronic address: veronica.salmaso@unipd.it.
  • 5 Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy. Electronic address: eleonora.cescon@phd.units.it.
  • 6 Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy. Electronic address: filippo.prencipe@units.it.
  • 7 Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy. Electronic address: daros@units.it.
  • 8 Centro de Investigaciones Biologicas, CSIC, Avenida Ramiro de Maeztu 9, 28040 Madrid, Spain; Centro de investigación biomédica en red en enfermedades neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Spain. Electronic address: loretomg@cib.csic.es.
  • 9 Centro de Investigaciones Biologicas, CSIC, Avenida Ramiro de Maeztu 9, 28040 Madrid, Spain; Centro de investigación biomédica en red en enfermedades neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Spain. Electronic address: ana.martinez@csic.es.
  • 10 Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy. Electronic address: spalluto@units.it.
  • 11 Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131 Padova, Italy. Electronic address: stefano.moro@unipd.it.
  • 12 Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy. Electronic address: sfederico@units.it.
PMID: 39059072 DOI: 10.1016/j.bioorg.2024.107659
Abstract

CK1δ is a serine-threonine kinase involved in several pathological conditions including neuroinflammation and neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Specifically, it seems that an inhibition of CK1δ could have a neuroprotective effect in these conditions. Here, a series of [1,2,4]triazolo[1,5-a][1,3,5]triazines were developed as ATP-competitive CK1δ inhibitors. Both positions 2 and 5 have been explored leading to a total of ten compounds exhibiting IC50s comprised between 29.1 µM and 2.08 µM. Three of the four most potent compounds (IC50 < 3 µM) bear a thiophene ring at the 2 position. All compounds have been submitted to computational studies that identified the chain composed of at least 2 atoms (e.g., nitrogen and carbon atoms) at the 5 position as crucial to determine a key bidentate hydrogen bond with Leu85 of CK1δ. Most potent compounds have been tested in vitro, resulting passively permeable to the blood-brain barrier and, safe and slight neuroprotective on a neuronal cell model. These results encourage to further structural optimize the series to obtain more potent CK1δ inhibitors as possible neuroprotective agents to be tested on models of the above-mentioned neurodegenerative diseases.

Keywords

ATP-competitive inhibitors; Amyotrophic Lateral Sclerosis; CK1; CK1δ; Neurodegenerative diseases; Neuroprotection; Parkinson’s disease; Protein kinase inhibitors; TDP-43; [1,2,4]triazolo[1,5-a][1,3,5]triazines.

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