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Review
. 2011 Jun;2(6):518-24.
doi: 10.18632/oncotarget.296.

A chemical biology approach to developing STAT inhibitors: molecular strategies for accelerating clinical translation

Erik A Nelson  1 , Sreenath V Sharma, Jeffrey Settleman, David A Frank
Affiliations
Review

A chemical biology approach to developing STAT inhibitors: molecular strategies for accelerating clinical translation

Erik A Nelson et al. Oncotarget. 2011 Jun.

Abstract

STAT transcription factors transduce signals from the cell surface to the nucleus, where they regulate the expression of genes that control proliferation, survival, self-renewal, and other critical cellular functions. Under normal physiological conditions, the activation of STATs is tightly regulated. In cancer, by contrast, STAT proteins, particularly STAT3 and STAT5, become activated constitutively, thereby driving the malignant phenotype of cancer cells. Since these proteins are largely dispensable in the function of normal adult cells, STATs represent a potentially important target for cancer therapy. Although transcription factors have traditionally been viewed as suboptimal targets for pharmacological inhibition, chemical biology approaches have been particularly fruitful in identifying compounds that can modulate this pathway through a variety of mechanisms. STAT inhibitors have notable anti-cancer effects in many tumor systems, show synergy with other therapeutic modalities, and have the potential to eradicate tumor stem cells. Furthermore, STAT inhibitors identified through the screening of chemical libraries can then be employed in large scale analyses such as gene expression profiling, RNA interference screens, or large-scale tumor cell line profiling. Data derived from these studies can then provide key insights into mechanisms of STAT signal transduction, as well as inform the rational design of targeted therapeutic strategies for cancer patients.

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Figures

Figure 1
Figure 1. Pyrimethamine reduces the viability of multiple myeloma cell lines containing activated STAT3
Cells were incubated with the indicated concentrations of pyrimethamine for 48 hours, after which the relative number of viable cells was measured using an ATP-dependent luminescence assay. Multiple myeloma cell lines containing activated STAT3 (U266 and INA6) or lacking activated STAT3 (H929 and RPMI 8226) were tested, as were peripheral blood mononuclear cells (PBMC) harvested from healthy donors.
Figure 2
Figure 2. Pimozide reduces STAT3 tyrosine phosphorylation in multiple myeloma cells
INA6 myeloma cells were incubated with the indicated concentrations of pimozide for three hours, after which whole cell lysates were analyzed by immunoblot for tyrosine phosphorylated STAT3 and total STAT3.
Figure 3
Figure 3. Myeloma cell viability is reduced when treated with the combination of pimozide and pyrimethamine
INA6 multiple myeloma cells were treated with pyrimethamine (pyr) or pimozide (pim) or both. After 48 hours, the relative number of viable cells was measured using an ATP-dependent luminescence assay.
Figure 4
Figure 4. High throughput cell line profiling reveals distinct tumor type sensitivity to pyrimethamine
684 human cancer cell lines were screened for the growth inhibitory effects of pyrimethamine, tested at three different concentrations, using previously described methods [26]. The tumor type enrichment algorithm indicates cell lines derived from different tumor types that show preferential sensitivity to pyrimethamine. 27% of the cell lines tested (vertical red line) were sensitive to pyrimethamine (defined as greater than 80% killing at 10 μ M). As a threshold for activity, greater than eight distinct cell lines of a particular tumor type had to show sensitivity to pyrimethamine (horizontal blue line). Tumor types in the top right hand quadrant are significantly more sensitive to the drug and are indicated by red filled circles.
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