Structure-Activity Relationship in the Leucettine Family of Kinase Inhibitors

被引：18

作者：

Tahtouh, Tania ^{[1
,2
]}

Durieu, Emilie ^{[1
,2
]}

Villiers, Benoit ^{[1
]}

Bruyere, Celine ^{[1
]}

Thu Lan Nguyen ^{[1
,3
,4
,5
]}

Fant, Xavier ^{[2
]}

Ahn, Kwang H. ^{[6
]}

Khurana, Leepakshi ^{[6
]}

Deau, Emmanuel ^{[1
]}

Lindberg, Mattias F. ^{[1
]}

Severe, Elodie ^{[1
]}

Miege, Frederic ^{[7
]}

Roche, Didier ^{[7
]}

Limanton, Emmanuelle ^{[8
]}

L'helgoual'ch, Jean-Martial ^{[8
]}

Burgy, Guillaume ^{[1
,8
]}

Guiheneuf, Solene ^{[8
]}

Herault, Yann ^{[3
,4
]}

Kendall, Debra A. ^{[6
]}

Carreaux, Francois ^{[8
]}

Bazureau, Jean-Pierre ^{[8
]}

Meijer, Laurent ^{[1
]}

机构：

[1] Manros Therapeut & Perha Pharmaceut, Perharidy Res Ctr, F-29680 Roscoff, Bretagne, France

[2] CNRS, Prot Phosphorylat & Human DiseaseGrp, Stn Biol Roscoff, F-29682 Roscoff, Bretagne, France

[3] Univ Strasbourg, Inst Genet & Biol Mol & Cellulaire, Dept Translat Med & Neurogenet, CNRS,UMR7104, Illkirch Graffenstaden, France

[4] INSERM U964, Illkirch Graffenstaden, France

[5] Rockefeller Univ, Lab Mol & Cellular Neurosci, New York, NY 10021 USA

[6] Univ Connecticut, Dept Pharmaceut Sci, Storrs, CT 06269 USA

[7] Edelris, F-69008 Lyon, France

[8] Univ Rennes 1, Inst Sci Chim Rennes ISCR UMR CNRS 6226, Campus Beaulieu, F-35042 Rennes, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 02期

关键词：

PHOSPHORYLATION-REGULATED KINASES; TAU EXON 10; DOWN-SYNDROME; ALZHEIMERS-DISEASE; DUAL-SPECIFICITY; MOUSE MODEL; NEUROFIBRILLARY DEGENERATION; PARKINSONS-DISEASE; DYRK1A INHIBITION; INCREASED DOSAGE;

D O I：

10.1021/acs.jmedchem.1c01141

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：1396 / 1417

页数：22

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