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The oncogenic transcription factor AP-1 (activator protein-1) is required for tumor promotion and progression. Identification of novel and specific AP-1 inhibitors would be beneficial for cancer prevention and therapy. The [...]

ABCG2 is a member of the adenosine triphosphate (ATP)-binding cassette family of multidrug transporters associated with resistance of tumor cells to many cytotoxic agents. Evaluation of modulators of ABCG2 activity [...]

A high‐throughput screening assay was developed and applied to a large library of natural product extract samples, in order to identify compounds which preferentially inhibited the in vitro 2D growth of a highly metastatic osteosarcoma cell line (MG63.3) compared to a cognate parental cell line (MG63) with low metastatic potential. Evaluation of differentially active natural product extracts with bioassay‐guided fractionation led to the identification of lovastatin (IC50 = 11 µm) and the limonoid toosendanin (IC50 = 26 nm). Other statins and limonoids were then tested, and cerivastatin was identified as a particularly potent (IC50 < 0.1 µm) and selective agent. These compounds potently and selectively induced apoptosis in MG63.3 cells, but not MG63. Assays with other cell pairs were used to examine the generality of these results. Statins and limonoids may represent unexplored opportunities for development of modulators of osteosarcoma metastasis. As cerivastatin was previously approved for clinical use, it could be considered for repurposing in osteosarcoma, pending validation in further models. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinase (MAPK) p38 is part of a broad and ubiquitously expressed family of MAPKs whose activity is responsible for mediating an intracellular response to extracellular stimuli through a phosphorylation cascade. p38 is central to this signaling node and is activated by upstream kinases while being responsible for activating downstream kinases and transcription factors via phosphorylation. Dysregulated p38 activity is associated with numerous autoimmune disorders and has been implicated in the progression of several types of cancer. A number of p38 inhibitors have been tested in clinical trials, with none receiving regulatory approval. One characteristic shared by all of the compounds that failed clinical trials is that they are all adenosine triphosphate (ATP)–competitive p38 inhibitors. Seeing this lack of mechanistic diversity as an opportunity, we screened ~32,000 substances in search of novel p38 inhibitors. Among the inhibitors discovered is a compound that is both non–ATP competitive and biologically active in cell-based models for p38 activity. This is the first reported discovery of a non–ATP-competitive p38 inhibitor that is active in cells and, as such, may enable new pharmacophore designs for both therapeutic and basic research to better understand and exploit non–ATP-competitive inhibitors of p38 activity. [ABSTRACT FROM AUTHOR]

The cancer stem cell marker, Ep CAM, is an important indicator of Wnt/β-catenin signaling activation and a functional component of hepatocellular tumor-initiating cells. A high-throughput screening assay was developed to identify inhibitors of Ep CAM-dependent growth of hepatocellular carcinoma (HCC) cells. Ep CAM(+) and Ep CAM(−) HCC cell lines were assessed for differential sensitivity to a Wnt/β-catenin pathway inhibitor. Libraries comprising 22 668 pure compounds and 107 741 crude or partially purified natural product extracts were tested, and 12 pure compounds and 67 natural product extracts were identified for further study. Three active compounds and the positive control were further characterized in terms of effects on Ep CAM expression. Treatment of Ep CAM(+) Hep3B cells resulted in loss of Ep CAM expression as assessed by flow cytometry. This reduction was incomplete (most cells continued to express Ep CAM), but resulted in generation of cell populations expressing lower levels of Ep CAM. Sublethal concentrations (~ IC50) reduced median Ep CAM expression to 28% of control after 1 day and 19% of control after 2 days. Reduction in Ep CAM expression preceded growth inhibition suggesting that a threshold of Ep CAM expression may be required for growth of Ep CAM-dependent cells. The identification of compounds with a variety of possible molecular targets suggests a likelihood of multiple mechanisms for modulation of Ep CAM-dependent cell growth. [ABSTRACT FROM AUTHOR]

An extract of the coralline demosponge Astrosclera willeyana inhibited the ubiquitin ligase activity of the immunomodulatory protein Cbl-b. The bioassay-guided separation of the extract provided ten active compounds, including three new N-methyladenine-containing diterpenoids, agelasines W–Y (1–3), a new bromopyrrole alkaloid, N(1)-methylisoageliferin (4), and six known ageliferin derivatives (5–10). The structures of the new compounds were elucidated from their spectroscopic and spectrometric data, including IR, HRESIMS, and NMR, and by comparison with spectroscopic data in the literature. While all of the isolated compounds showed Cbl-b inhibitory activities, ageliferins (4–10) were the most potent metabolites, with IC50 values that ranged from 18 to 35 μM. [ABSTRACT FROM AUTHOR]