Discovery of a Novel Small-molecule Interleukin-6 Inhibitor through Virtual Screening Using Artificial Intelligence

Background: Interleukin-6 (IL-6) is a multifunctional cytokine involved in various cell functions and diseases. Thus far, several IL-6 inhibitors, such as humanized monoclonal antibody have been used to block excessive IL-6 signaling causing autoimmune and inflammatory diseases. However, anti-IL-6 and anti-IL-6 receptor monoclonal antibodies have some clinical disadvantages, such as a high cost, unfavorable injection route, and tendency to mask infectious diseases. While a small-molecule IL-6 inhibitor would help mitigate these issues, none are currently available. Objective: The present study evaluated the biological activities of identified compounds on IL-6 stimulus. Methods: We virtually screened potential IL-6 binders from a compound library using INTerprotein's Engine for New Drug Design (INTENDD (R)) followed by the identification of more potent IL-6 binders with artificial intelligence (AI)-guided INTENDD (R). The biological activities of the identified compounds were assessed with the IL-6-dependent cell line 7TD1. Results: The compounds showed the suppression of IL-6-dependent cell growth in a dose-dependent manner. Furthermore, the identified compound inhibited expression of IL-6-induced phosphorylation of signal transducer and activator of transcription 3 in a dose-dependent manner. Conclusion: Our screening compound demonstrated an inhibitory effect on IL-6 stimulus. These findings may serve as a basis for the further development of small-molecule IL-6 inhibitors.

Automated summary

This study evaluated the biological activities of a new small-molecule IL-6 inhibitor. The compounds showed inhibition of IL-6-dependent cell growth and suppressed IL-6-induced signaling pathway. These findings provide a basis for further development of small-molecule IL-6 inhibitors.