2. Academic Validation
  3. Structure-Activity Relationship in the Leucettine Family of Kinase Inhibitors

Structure-Activity Relationship in the Leucettine Family of Kinase Inhibitors

  • J Med Chem. 2022 Jan 27;65(2):1396-1417. doi: 10.1021/acs.jmedchem.1c01141.
Tania Tahtouh 1 2 3,  Emilie Durieu 1 2,  Benoît Villiers 1,  Céline Bruyère 1,  Thu Lan Nguyen 1 4 5,  Xavier Fant 2,  Kwang H Ahn 6,  Leepakshi Khurana 6,  Emmanuel Deau 1,  Mattias F Lindberg 1,  Elodie Sévère 1,  Frédéric Miege 7,  Didier Roche 7,  Emmanuelle Limanton 8,  Jean-Martial L'Helgoual'ch 8,  Guillaume Burgy 1 8,  Solène Guiheneuf 8,  Yann Herault 4,  Debra A Kendall 6,  François Carreaux 8,  Jean-Pierre Bazureau 8,  Laurent Meijer 1
Affiliations

Affiliations

  • 1 Manros Therapeutics & Perha Pharmaceuticals, Perharidy Research Center, 29680 Roscoff, Bretagne, France.
  • 2 CNRS, 'Protein Phosphorylation and Human Disease' Group, Station Biologique De Roscoff, Place G. Teissier, Bp 74, 29682 Roscoff, Bretagne, France.
  • 3 College Of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates.
  • 4 Institut De Génétique Et De Biologie Moléculaire et Cellulaire, Department of Translational Medicine and Neurogenetics, Université de Strasbourg, CNRS UMR7104 & INSERM U964, 67400 Illkirch, France.
  • 5 Laboratory of Molecular & Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10021-6399, United States.
  • 6 Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Storrs, Connecticut 06269, United States.
  • 7 Edelris, Bâtiment Bioserra 1, 60 avenue Rockefeller, 69008 Lyon, France.
  • 8 Institut des Sciences Chimiques de Rennes ISCR-UMR CNRS 6226, Université de Rennes 1, Campus de Beaulieu, Bât. 10A, CS 74205, 263 Avenue du Général Leclerc, 35042 Rennes Cedex, France.
PMID: 34928152 DOI: 10.1021/acs.jmedchem.1c01141
Abstract

The protein kinase DYRK1A is involved in Alzheimer's disease, Down syndrome, diabetes, viral infections, and leukemia. Leucettines, a family of 2-aminoimidazolin-4-ones derived from the marine Sponge alkaloid Leucettamine B, have been developed as pharmacological inhibitors of DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases). We report here on the synthesis and structure-activity relationship (SAR) of 68 Leucettines. Leucettines were tested on 11 purified kinases and in 5 cellular assays: (1) CLK1 pre-mRNA splicing, (2) Threonine-212-Tau phosphorylation, (3) glutamate-induced cell death, (4) Autophagy and (5) antagonism of ligand-activated Cannabinoid Receptor CB1. The Leucettine SAR observed for DYRK1A is essentially identical for CLK1, CLK4, DYRK1B, and DYRK2. DYRK3 and CLK3 are less sensitive to Leucettines. In contrast, the cellular SAR highlights correlations between inhibition of specific kinase targets and some but not all cellular effects. Leucettines deserve further development as potential therapeutics against various diseases on the basis of their molecular targets and cellular effects.

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