In this project, Interprotein identified a good small molecule-binding site that is located on the important surface for interaction of interleukin-6 (IL-6) and IL-6 receptor α (IL-6Rα ). We also conduct the design of the compounds that were expected to bind to the pocket as well as several wet assessments and have already identified a series of interesting hit-to-lead compound, named "CIA series compounds", with the following pharmaceutical profiles:
- CIA series compounds have been shown to inhibit the binding of IL-6 to IL-6Rα by surface plasmon resonance (SPR) analysis.
- The active compounds were confirmed to bind to the target protein (IL-6) by SPR analysis.
- A part of the active compounds were demonstrated to interact with the proposed binding site of the target protein by nuclear magnetic resonance (NMR) analysis.*.
*IL-6 inhibitor project was adopted as a theme of "RIKEN Program for Drug Discovery and Medical Technology Platform" and these results were obtained by the collaborative research with RIKEN
- The active compounds were demonstrated to inhibit IL-6-stimulated phosphorylation of STAT3 in Hep3B cells (human hepatic cell line).
Small molecule IL-6 inhibitor is expected to contribute to treatment for not only Castleman's disease, rheumatoid arthritis and juvenile idiopathic arthritis (current indications of tocilizumab) but also many other inflammatory/autoimmune diseases including CNS inflammation (with CNS-penetrative small compounds) and cancer-related cachexia. We also bring IL-6-related leukemia and solid tumors into view.