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 M 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 C␤2 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 M) 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.

Characterization of p70 S6 kinase 1 in early development of mouse embryos

“…Dimethyl sulfoxide (DMSO) vehicle increasing the solubility of rapamycin was added (final concentration of DMSO < 0.5%) to culture the mouse one-cell embryos (Stevenson et al, 2002). After 24 hr incubation, we examined the percentage of the embryo cleavage at different rapamycin concentrations (0, 2.5, 5, and 10 lg/ml).…”

Inhibition of polo like kinase 1 in sarcomas induces apoptosis that is dependent on Mcl-1 suppression

“…Similar to aurora kinases, PLK-1 has also been shown to be important in cell proliferation and its overexpression in various human cancers appears to be sufficient to override cellular checkpoints and induce genetic instability, promoting tumorigenesis. [5][6][7] The first small molecule inhibitor of PLK-1 was scytonemin 26 followed by BI2536, 27 and ON01910, 28 which has been tested in phase I and II clinical studies. The present study is an attempt to determine whether inhibition of PLK-1 by TAK-960 could represent an effective new therapeutic strategy in the treatment of sarcoma and to allow us to further understand how the inhibition of PLK-1 leads to cell death.…”

Plk1-Targeted Small Molecule Inhibitors: Molecular Basis for Their Potency and Specificity

“…Scytonemin has been shown to inhibit the ability of Plk1 to phosphorylate Cdc25C in a concentrationdependent manner with an in vitro IC 50 of 2 ± 0.1 μM (McInnes et al, 2006;Stevenson et al, 2002). However, it was later turned out to be a nonselective molecule that also inhibits myelin transcription factor 1 (MYT1), cyclin-dependent kinase 1 (CDK1), checkpoint kinase 1 (CHK1), and protein kinase C (PKC) with similar potencies (McInnes et al, 2005).…”