Interleukin 6 and the signal transducer and activator of transcription (STAT) 3
proteins have important roles in
cancer cell survival and proliferation. Recent studies demonstrate that abnormal STAT3 activation promotes
tumor growth and supports survival of many human
cancers, and thus, this
protein or the pathway responsible for its activation is a potential target for the new anticancer
therapy. STAT3 is
a DNA binding
transcription factor, and therefore, its function depends on nuclear translocation. To discover inhibitors of the STAT3 pathway, we designed a cell-based screening assay capable of identifying small molecules that inhibit nuclear translocation. Among the 2000-compound National Cancer Institute Diversity set, we identified 8-benzyl-4-oxo-8-azabicyclo[3.2.1]oct-2-ene-6,7-dicarboxylic
acid (SD-1008) as a micromolar inhibitor of
interleukin-6 or oncostatin-induced STAT3 nuclear translocation. In addition,
SD-1008 inhibits tyrosyl phosphorylation of STAT3,
Janus kinase 2 (JAK2), and Src.
SD-1008 also reduces STAT3-dependent
luciferase activity. Biochemical studies with recombinant JAK2
proteins demonstrate that high concentrations of
SD-1008 directly inhibit JAK2
kinase autophosphorylation. Exposure of various cell lines to
SD-1008 decreases levels of the STAT3-dependent
proteins, Bcl-X(L) and
survivin, inducing apoptosis.
SD-1008 also enhances apoptosis induced by
paclitaxel in
ovarian cancer cells. These results demonstrate that
SD-1008 directly blocks the JAK-STAT3 signaling pathway in human
cancer cells that express constitutively active Stat and add to the growing literature that identifies this pathway as a viable target for
drug development. Finally,
SD-1008 may be a suitable prototype for further chemical modification and exploration as a therapeutic agent.