The Identification and Characterization of the Marine Natural Product Scytonemin as a Novel Antiproliferative Pharmacophore

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 303; no. 2; pp. 858 - 866
• Main Authors: Stevenson, Christopher S, Capper, Elizabeth A, Roshak, Amy K, Marquez, Brian, Eichman, Chris, Jackson, Jeffrey R, Mattern, Michael, Gerwick, William H, Jacobs, Robert S, Marshall, Lisa A
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.11.2002
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; CDC2 Protein Kinase - antagonists & inhibitors; Cell Cycle Proteins; Cell Division - drug effects; Cyclic AMP-Dependent Protein Kinases - metabolism; Cyclin B - antagonists & inhibitors; Enzyme Inhibitors - pharmacology; Glutathione Transferase - antagonists & inhibitors; Glutathione Transferase - metabolism; Humans; Indoles - isolation & purification; Indoles - pharmacology; Jurkat Cells; Kinetics; Phenols - isolation & purification; Phenols - pharmacology; Polo-Like Kinase 1; Protein Kinase C - metabolism; Protein Kinase Inhibitors; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.102.036350

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 μM 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 Cβ2 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 μM) 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.