Fbxo3 is a ubiquitin E3 ligase F box component, which potently stimulates cytokine secretion from human inflammatory cells by mediating the degradation of the TRAF
inhibitory protein, Fbxl2. BC-1215 is a highly unique, selective Fbxo3 inhibitor with an estimated IC50 value of 10-7M, measured by prevention of SCFFbxo3 catalyzed Fbxl2 ubiquitination in vitro. BC-1215 exhibited maximal inhibitory binding at 10-7M, measured by quantification of bound Fbxl2 protein. As the inhibition of Fbxo3, the known Fbxl2 substrates including cyclin D2, cyclin D3, and cytidylyl-transferase were decreased in MLE cells treated with BC-1215 at 10μM and 50μM for 16h. The suppression of upregulated levels of TRAF2 and TRAF3, along with activating the downstream p38 and phospho-IKK in the NF-kB pathway, by TNF treatment could also be observed in MLE cells treated with 10μg/ml BC-1215 for 6h. BC-1215 reversibly inhibited Fbxo3 resulting in destabilized TRAF proteins. Intraperitoneal injection with BC-1215 at doses of 0.8, 4, 20, 100 and 500μg/kg, 10 minutes prior to LPS challenge, dose-dependently inhibited the release of IL-1b, IL-6, and TNF-α in blood of mice. In vivo administration of BC-1215 effectively lessened the severity of viral pneumonia, septic shock, colitis, and cytokine-driven inflammation systemically in murine models.
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