IL-6 is a member of the gp130-related cytokine family, which plays an important role in IL-6/GP130/STAT3 signaling pathway[1]. IL-6 firstly binds to IL6 receptor α (IL-6Rα), which recruits GP130 on cell membrane; then dimerization of two of the IL6/IL-6Rα/GP130 trimers allows signal transduction via GP130 cytoplasmic doamins, which activates Jak1 then STAT3 (Tyr705 phosphorylation), leading to STAT3 nucleus translocation, DNA binding, and multiple oncogene transcriptions[2]. IL-6/GP130/STAT3 signaling pathway was previously found to be protumorigenic in many cancers[3]. To date, very few small molecules have been identified as IL6/gp130 inhibitor[4, 5]. In our lab, by using computational modeling, we were able to find the key binding sites on the interaction surface between IL-6 and GP130 D1 domain. Based on this knowledge, we designed novel small molecule IL-6/GP130 inhibitors with different molecular scaffolds by implementing MLSD (multiple ligand simultaneous docking)[6,7,8] and other structure based drug design strategies. These small molecule IL6/gp130 inhibitors were synthesized in our lab and preliminary biological tests have shown that they are able to specifically inhibit the IL-6/GP130/STAT3 pathway and thus effectively kill several types of cancer cells.

Rational design, synthesis and evaluation of small molecule IL-6/GP130 inhibitors as anticancer agents

251st National Meeting (2016)

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