title: Kinase inhibitor scaffolds against neurodegenerative diseases from a Southern Australian ascidian, Didemnum sp.
abstract: Screening a library of Southern Australian and Antarctic marine invertebrates and algae for inhibitors of neurodegenerative disease kinase targets casein kinase 1 (CK1δ), cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β) identified a Western Australian Didemnum species (CMB-02127) as a high-priority specimen. Chemical fractionation returned the known aromatic alkaloids ningalins B-D as the major metabolites, together with six minor metabolites, the new ningalins E-G and the known hexacyclic pyrrole alkaloids lamellarins Z, G and A6. All structures were assigned by detailed spectroscopic analysis and literature comparisons, and the structural assignments were supported by biosynthetic considerations. The ningalins showed potent and broad inhibition across the three kinases, while the lamellarins were generally more selective for CDK5. Docking studies using published X-ray crystal structures of CDK5 revealed both scaffolds target the ATP binding pocket.
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Fabien
authors.initials: F
authors.lastname: Plisson
authors.forename: Melissa
authors.initials: M
authors.lastname: Conte
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Khalil
authors.forename: Xiao-Cong
authors.initials: XC
authors.lastname: Huang
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Piggott
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Capon
mesh_terms: D000818:Animals; D001315:Australia; D001665:Binding Sites; D002227:Carbazoles / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors / Q000378:metabolism; D002396:Catechols / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D003374:Coumarins / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D014561:Urochordata / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002227:Carbazoles; D002396:Catechols; D003374:Coumarins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C575177:ningalin E; C575178:ningalin F; C575179:ningalin G; D048148:Casein Kinase Idelta; D051360:Cyclin-Dependent Kinase 5; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3