title: Selectivity, cocrystal structures, and neuroprotective properties of leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B.
abstract: DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) are implicated in the onset and development of Alzheimer's disease and Down syndrome. The marine sponge alkaloid leucettamine B was recently identified as an inhibitor of DYRKs/CLKs. Synthesis of analogues (leucettines) led to an optimized product, leucettine L41. Leucettines were cocrystallized with DYRK1A, DYRK2, CLK3, PIM1, and GSK-3β. The selectivity of L41 was studied by activity and interaction assays of recombinant kinases and affinity chromatography and competition affinity assays. These approaches revealed unexpected potential secondary targets such as CK2, SLK, and the lipid kinase PIKfyve/Vac14/Fig4. L41 displayed neuroprotective effects on glutamate-induced HT22 cell death. L41 also reduced amyloid precursor protein-induced cell death in cultured rat brain slices. The unusual multitarget selectivity of leucettines may account for their neuroprotective effects. This family of kinase inhibitors deserves further optimization as potential therapeutics against neurodegenerative diseases such as Alzheimer's disease.
authors.affiliation: CNRS, "Protein Phosphorylation & Human Disease" Group, Station Biologique, 29680 Roscoff, Bretagne, France.
authors.forename: Tania
authors.initials: T
authors.lastname: Tahtouh
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Elkins
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Meera
authors.initials: M
authors.lastname: Soundararajan
authors.forename: Guillaume
authors.initials: G
authors.lastname: Burgy
authors.forename: Emilie
authors.initials: E
authors.lastname: Durieu
authors.forename: Claude
authors.initials: C
authors.lastname: Cochet
authors.forename: Ralf S
authors.initials: RS
authors.lastname: Schmid
authors.forename: Donald C
authors.initials: DC
authors.lastname: Lo
authors.forename: Florent
authors.initials: F
authors.lastname: Delhommel
authors.forename: Anselm E
authors.initials: AE
authors.lastname: Oberholzer
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
authors.forename: François
authors.initials: F
authors.lastname: Carreaux
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bazureau
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002846:Chromatography, Affinity; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry; D004149:Dioxoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011161:Porifera / Q000737:chemistry*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000097603:Dyrk Kinases
chemical_list: D000470:Alkaloids; D016564:Amyloid beta-Protein Precursor; D051357:Cyclin-Dependent Kinase 2; D004149:Dioxoles; D018698:Glutamic Acid; D007093:Imidazoles; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011994:Recombinant Proteins; D000097603:Dyrk Kinases; C578491:((5Z)5-(1,3-benzodioxol-5-yl)methylene-2-phenylamino-3,5-dihydro-4H-imidazol-4-one)