title: The identification and characterization of the marine natural product scytonemin as a novel antiproliferative pharmacophore.
abstract: Marine natural products provide a rich source of chemical diversity that can be used to design and develop new, potentially useful therapeutic agents. We report here that scytonemin, a pigment isolated from cyanobacteria, is the first described small molecule inhibitor of human polo-like kinase, a serine/threonine kinase that plays an integral role in regulating the G(2)/M transition in the cell cycle. Scytonemin inhibited polo-like kinase 1 activity in a concentration-dependent manner with an IC(50) of 2 microM against the recombinant enzyme. Biochemical analysis showed that scytonemin reduced GST-polo-like kinase 1 activity in a time-independent fashion, suggesting reversibility, and with a mixed-competition mechanism with respect to ATP. Although scytonemin was less potent against protein kinase A and Tie2, a tyrosine kinase, it did inhibit other cell cycle-regulatory kinases like Myt1, checkpoint kinase 1, cyclin-dependent kinase 1/cyclin B, and protein kinase Cbeta2 with IC(50) values similar to that seen for polo-like kinase 1. Consistent with these effects, scytonemin effectively attenuated, without chemical toxicity, the growth factor- or mitogen-induced proliferation of three cell types commonly implicated in inflammatory hyperproliferation. Similarly, scytonemin (up to 10 microM) was not cytotoxic to nonproliferating endotoxin-stimulated human monocytes. In addition, Jurkat T cells treated with scytonemin were induced to undergo apoptosis in a non-cell cycle-dependent manner consistent with its activities on multiple kinases. Here we propose that scytonemin's dimeric structure, unique among natural products, may be a valuable template for the development of more potent and selective kinase inhibitors used for the treatment of hyperproliferative disorders.
authors.affiliation: Department of Ecology, Evolution, and Marine Biology, University of California at Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Stevenson
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Capper
authors.forename: Amy K
authors.initials: AK
authors.lastname: Roshak
authors.forename: Brian
authors.initials: B
authors.lastname: Marquez
authors.forename: Chris
authors.initials: C
authors.lastname: Eichman
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jackson
authors.forename: Michael
authors.initials: M
authors.lastname: Mattern
authors.forename: William H
authors.initials: WH
authors.lastname: Gerwick
authors.forename: Robert S
authors.initials: RS
authors.lastname: Jacobs
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Marshall
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019926:Cyclin B / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000302:isolation & purification / Q000494:pharmacology*; D019169:Jurkat Cells; D007700:Kinetics; D010636:Phenols / Q000302:isolation & purification / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D019926:Cyclin B; D004791:Enzyme Inhibitors; D005982:Glutathione Transferase; D007211:Indoles; D010636:Phenols; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C083368:scytonemin