UC San Diego
2-Nitrofuran Arylamide Compounds as Innate Immune Modulators
- Author(s): Fujita, Yuya
- Advisor(s): Corr, Mary P
- Hedrick, Stephen M
- et al.
Autoimmune diseases such as rheumatoid arthritis affect millions of patients and many of these diseases have yet to find a cure. Transcription factors like nuclear factor-κB (NF-κB) play an important role in chronic inflammatory diseases. While previously investigated as a drug target, NF-κB inhibitors have failed due to adverse effects observed in clinical studies likely due to impairment of cellular homeostasis and increased toxicity resulting from complete NF-κB inhibition. We aimed to identify immunosuppressant
compounds by reanalyzing data from a prior high-throughput screen using a cell-based NF-κB reporter assay in human monocytic THP-1 cells with a 166,304 compound library. Candidate compounds were screened for suppression of LPS-induced NF-κB activity. We identified 270 hit compounds through a naïve “Top X” approach. These compounds were further analyzed for their effects on cellular viability and cytokine production in human and murine cell lines. Compounds from the 2-nitrofuran arylamide compounds reduced TNFα, IFNβ, and IP10 effectively when ligands for TLR3, TLR7, TLR9, and STING were used as a primary stimulus. In a preliminary study, treatment with two of these compounds prevented the onset of allodynia but do not change swelling in a K/BxN mouse model. Further analysis of these compounds and this chemical family may yield potential drug therapies to treat patients afflicted with autoimmune disorders associated with the overproduction of innate cytokines.