Vol. 303, Issue 2, 858-866, November 2002

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

Christopher S. Stevenson, Elizabeth A. Capper, Amy K. Roshak, Brian Marquez, Chris Eichman, Jeffrey R. Jackson, Michael Mattern, William H. Gerwick, Robert S. Jacobs and Lisa A. Marshall

Department of Ecology, Evolution, and Marine Biology, University of California at Santa Barbara, Santa Barbara, California (C.S.S., R.S.J.); Departments of Respiratory, Inflammation, and Respiratory Pathogens (E.A.C., A.K.R., C.E.), Cardiovascular, Urogenital, and Oncology (J.R.J., M.M.), and Project Management (L.A.M.), GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania; and College of Pharmacy, Oregon State University, Corvallis, Oregon (B.M., W.H.G.)

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 G₂/M transition in the cell cycle. Scytonemin inhibited polo-like kinase 1 activity in a concentration-dependent manner with an IC₅₀ 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 C2 with IC₅₀ 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.