Structure-Activity Relationship in the Leucettine Family of Kinase Inhibitors
Tania Tahtouh
(1, 2, 3)
,
Emilie Durieu
(1, 2)
,
Benoit Villiers
(1)
,
Celine Bruyere
(1)
,
Thu Lan Nguyen
(4, 5, 6, 1)
,
Xavier Fant
(2)
,
Kwang H. Ahn
(7)
,
Leepakshi Khurana
(7)
,
Emmanuel Deau
(1)
,
Mattias F. Lindberg
(1)
,
Elodie Severe
(1)
,
Frederic Miege
(8)
,
Didier Roche
(8)
,
Emmanuelle Limanton
(9)
,
Jean-Martial L'Helgoual'Ch
(9)
,
Guillaume Burgy
(9, 1)
,
Solene Guiheneuf
(9)
,
Yann Hérault
(4, 5)
,
Debra A. Kendall
(7)
,
François Carreaux
(9)
,
Jean-Pierre Bazureau
(9)
,
Laurent Meijer
(1)
1
ManRos Therapeutics
2 SBR - Station biologique de Roscoff = Roscoff Marine Station
3 ADU - Abu Dhabi University
4 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
5 CBI - Centre for Integrative Biology
6 Rockefeller University [New York]
7 UCONN - University of Connecticut
8 Edelris
9 ISCR - Institut des Sciences Chimiques de Rennes
2 SBR - Station biologique de Roscoff = Roscoff Marine Station
3 ADU - Abu Dhabi University
4 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
5 CBI - Centre for Integrative Biology
6 Rockefeller University [New York]
7 UCONN - University of Connecticut
8 Edelris
9 ISCR - Institut des Sciences Chimiques de Rennes
Yann Hérault
- Fonction : Auteur
- PersonId : 741744
- IdHAL : yann-herault
- ORCID : 0000-0001-7049-6900
- IdRef : 077172639
Jean-Pierre Bazureau
- Fonction : Auteur
- PersonId : 941300
- ORCID : 0000-0003-3053-3425
Laurent Meijer
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- Fonction : Auteur correspondant
- PersonId : 1144195
- ORCID : 0000-0003-3511-4916
- IdRef : 059806761
Connectez-vous pour contacter l'auteur
Résumé
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 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.