The IL-6/JAK/STAT pathway is a key signal transduction pathway activated in many cancers which results in the translocation of phosphorylated STAT dimers to the nucleus where they regulate gene transcription. The process is activated by interleukin-6 (IL-6) through an IL-6/GP130 homodimerization event. Inhibition of this homodimerization and subsequent disruption of downstream phosphorylation would provide a new target for cancer therapy.   Therefore, two series of compounds (indoline- and indole-containing scaffolds) were initially designed and synthesized based on the structure of madindoline A, a weak inhibitor of IL-6. Molecular modeling suggests their binding to the D1 domain of GP130, thereby preventing interaction with IL-6. These results are supported through binding studies with the GP130 protein and observed inhibition of pSTAT3. Subsequent modification has led to additional compounds which effectively inhibit the pathway. The design, synthesis, and biological evaluation of these analogues in various cell lines will be reported and discussed.

Small molecules targeting IL-6/GP130 homodimerization in the IL-6/JAK/STAT pathway

243rd National Meeting (2012)

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