Modulators of STAT Transcription Factors for the Targeted Therapy of Cancer (STAT3 Activators)

The signal transducer and activator of transcription (STAT) family of transcription factors transduce signals from a variety of extracellular stimuli, and are important mediators of inflammation, cell survival, differentiation, and proliferation. STATs are activated in response to growth factors, cytokines, and G-CSF binding to cell surface Receptor Tyrosine Kinases. Although structurally similar, the seven STAT family members possess diverse biological roles. For example, STAT1 activation is pro-inflammatory and anti-proliferative, while STAT3 activation is anti-inflammatory and pro-apoptotic. Studies show that STAT3 is activated in a majority of breast and prostate cancers, and that STAT3 inhibition using RNA interference or a dominant negative leads to reduced cell proliferation, survival, and wound healing. Further, blocking STAT3 interaction with the epidermal growth factor receptor (EGFR) using peptide Aptamers has been shown to reduce tumor growth. Due to the diverse roles and potent phenotypes associated with STAT signaling, the identification of selective potentiators of STAT3 activity may lead to pharmacological tools for Cancer, wound healing, and inflammatory diseases. In response to the chief goal of this project, the identified small molecular probe ML115 (CID-619100 is a potent and selective activator of transcription 3 (STAT3), with a low nanomolar EC50 for STAT3, and is inactive against the related STAT1 and NFκB anti-targets. QPCR experiments further confirm that the probe upregulates transcription of the oncogene BCL3. In addition, the probe does not exhibit cytotoxicity in the parental cell lines used for the STAT3 assay (HT-1080) and STAT1 assay (NIH-3T3).