Interleukin-6 (IL-6) is a pleiotropic cytokine responsible for the regulation of many different cellular processes, including acute-phase response, cell proliferation, and T and B cell proliferation and differentiation. IL-6 is upregulated in many different disease states, including autoimmune diseases, chronic inflammatory diseases, and cancers, which makes it a desirable target for the treatment of these diseases. Currently, the only approved drug for treating this pathway is tocilizumab, which is a monoclonal antibody. While tocilizumab performs well, it must be given intravenously or via an injection. This, combined with its status as a biologic drug, makes it an unattractive treatment in terms of cost and administration. Therefore, it would be considered advantageous to produce a small molecule inhibitor drug of IL-6, which would decrease the cost and increase the ease of drug administration.<br/><br/>To pursue this end, the Li lab has endeavored to utilize a structure-based approach to design and synthesize a class of small molecule inhibitors. Through docking and molecular dynamics simulations, key pockets and residues in glycoprotein 130 (GP130), to which IL-6 must bind for signaling, have been identified. From this finding, several generations of IL-6 pathway-selective inhibitors have been developed, with the most recent generation possessing single-digit micromolar affinity. The most recent developments have been towards the optimization of the synthesis of these selective inhibitors as well as towards the development of the next generation of inhibitors that will ideally possess sub-micromolar affinity. Cellular studies have confirmed their targeting efficacy and selectivity.

Structure-based drug design towards small molecule interleukin-6 inhibitors

2019 Spring National Meeting

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