TY - JOUR T1 - The Identification and Characterization of the Marine Natural Product Scytonemin as a Novel Antiproliferative Pharmacophore JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 858 LP - 866 DO - 10.1124/jpet.102.036350 VL - 303 IS - 2 AU - Christopher S. Stevenson AU - Elizabeth A. Capper AU - Amy K. Roshak AU - Brian Marquez AU - Chris Eichman AU - Jeffrey R. Jackson AU - Michael Mattern AU - William H. Gerwick AU - Robert S. Jacobs AU - Lisa A. Marshall Y1 - 2002/11/01 UR - http://jpet.aspetjournals.org/content/303/2/858.abstract N2 - 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 inhibitedpolo-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 Cβ2 with IC50 values similar to that seen forpolo-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. The American Society for Pharmacology and Experimental Therapeutics ER -