IL-6 inhibitor

In this project, Interprotein identified a binding site that is located on the important surface for interaction of interleukin-6 (IL-6) and IL-6 receptor (IL-6R), and to which small molecule compounds can bind, then designed the compounds that would bind to the pocket by closest packing approach for drug design (CPADD) method. Structures of the compounds generated by CPADD method were eventually narrowed down to 140 compounds and these compounds were actually screened by biological assay systems. Based on the results, plural compounds with different scaffolds were identified as hit compounds, and their derivatives were synthesized and evaluated from the views of pharmacological and early ADMET profiles in part.

Subsequently, we focused on especially one scaffold and its analogues/derivatives on a basis of potency for the inhibition of lymphoid cell proliferation, then designed and synthesized new derivatives aiming for preservation or augmentation of affinity and improvement of physicochemical properties. Obtained compounds showed very interesting profiles as follows:

1. On the basis of the results described above, we designed and synthesized a series of compounds, which were named "CIA series compounds".
   
   
2. Plural CIA series compounds have been shown to inhibit the binding of IL-6 to IL-6R by surface plasmon resonance (SPR) analysis.
   
   
3. The active compounds were confirmed to bind to the target protein by SPR analysis.
   
   
4. 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.
   
   
5. A part of the active compounds was demonstrated to inhibit IL-6-stimulated expression of C-reactive protein (CRP) mRNA in Hep3B cells (human hepatoma 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 cachexia and many kinds of inflammatory/autoimmune diseases.