BC-1215, a FBXO3 Inhibitor, Reduces Severity of Cytokine-Driven Inflammation

FBXOs (F-box proteins) is an F-box domain-containing proteins, mediate protein-protein interactions. They play a role in cellular functions, like signal transduction and cell cycle. Different mechanisms can regulate FBXO levels through the protein degradation process and association with the SCF complex.

FBXO3 is a component of a ubiquitin E3 ligase. It destabilizes FBXL2, a TRAF inhibitor to induce cytokine secretion from human inflammatory cells.

FBXL2 (F-box/LRR-repeat protein 2) belongs to the F-box proteins. It is a highly conserved phosphoprotein. Interestingly, FBXO3 targets phosphoprotein. Consequently, FBXO3 targets FBXL2 and induces its ubiquitination. Furthermore, FBXL2 inhibits TRAF, which participates in inflammation and immune responses. Once FBXL2 ubiquitination occurs, TRAF will exhibit high levels, and subsequently cause inflammation.

Herein, we will discuss the bioactivity of an FBXO3 inhibitor, BC-1215. The compound has a high affinity to FBXO3-ApaG, with an IC50 value of 0.9 μg/mL. It decreases FBXO3-FBXL2 interaction and inhibits FBXL2 ubiquitination catalyzed by SCFFBXO3. Meanwhile, BC-1215 reduces TRAF 1-6 protein levels. However, BC-1215 shows no effect on TRAF steady-state mRNA levels.

According to the potential activity in vitro, researchers go on to further study in animals. As a result, BC-1215 exhibits anti-inflammatory activity. Mice treated with cecal ligation and puncture, displays increased cytokine release. After BC-1215 treatment, they dramatically reduce pro-inflammatory cytokines. Moreover, BC-1215 modestly suppresses bacterial growth and decreases counts of bacteria. Furthermore, the inhibitor exhibits similar effects in an H1N1 pneumonia model.

1. NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase; Nox)