Stat3 is a nuclear transcription factor required for regulating genes involved in proliferation, apoptosis, angiogenesis and invasion, in addition to genes encoding cytokines, chemokines and growth factors. In contrast to the transient nature of Stat3 activation in normal cells, many human cancers harbor constitutive Stat3 activity. Stat3 downstream target genes are critical to the dysregulated biological processes that promote tumor cell growth, survival and induce chemoresistance, thus targeting Stat3 signaling represents an important therapeutic target in cancer therapy.We have rationally designed and developed Stat3 inhibitors that disrupt transcriptionaly active Stat3�Stat3 homo-dimers, suppress Stat3 activation (phosphorylation), inhibit Stat3-target gene expression (c-Myc, Bcl-xL, survivin) and potently induce apoptosis in brain tumor cells harboring aberrant Stat3 activity. Moreover, lead compound SH-4-54, a non-phosphorylated small molecule, demonstrated in vivo blood-brain barrier permeability, potent inhibition of Stat3 phosphorylation in vivo and induced strong anti-tumor effects against the most aggressive and lethal glioblastomas.

Progress towards small-molecule, non-phosphorylated STAT3 inhibitors

245th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.