A Chemical Biology Approach to Developing STAT Inhibitors: Molecular Strategies for Accelerating Clinical Translation
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1Department of Medical Oncology, Dana-Farber Cancer Institute, Departments of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02215
2Massachusetts General Hospital, Harvard Medical School
3Oncology Drug Discovery, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139
Keywords: STAT transcription factors; signal transduction; cancer therapy
Received: June 14, 2011; Accepted: June 15, 2011; Published: June 15, 2011;
David A. Frank, email:
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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