Screening approaches to generating STAT inhibitors: Allowing the hits to identify the targets.

STAT transcription factors are regulators of critical cellular processes such as proliferation, survival, and self-renewal. While the activity of these proteins is tightly regulated under physiological conditions, they can become constitutively activated in a broad range of human cancers. This inappropriate STAT activation leads to enhanced transcription of genes that can directly lead to the malignant phenotype. Since STATs are largely dispensable for normal cell function, this has raised the possibility that STATs might be key targets for cancer therapy. Although a number of structure-based strategies have been used to develop STAT inhibitors, an alternate approach is to use cell-based assays that make use of the transcriptional function of STATs. Employing these systems, one can screen large chemical libraries to identify compounds that specifically block the function of a given STAT. This approach can lead to the identification of compounds that inhibit STATs by a variety of mechanisms, and can suggest novel targets for therapy. This type of functional screening strategy has already identified a drug that potently inhibits STAT3, and which is now being evaluated in a clinical trial for patients with chronic lymphocytic leukemia.