KB-0118 (BBC0115) is an inhibitor targeting the BET bromodomain. It selectively binds to BRD2 and BRD4, with dissociation constants (Kd) of 36.7 μM for BRD2 BD1 and 47.4 μM for BRD4 BD1, while not binding to BRD3. KB-0118 suppresses the secretion of pro-inflammatory cytokines such as TNF, IL-1β, and IL-23a, and selectively inhibits Th17 cell differentiation. The compound regulates Th17-driven inflammation through the epigenetic suppression of BRD4, as evidenced by the downregulation of STAT3 and BRD4 target genes. Additionally, KB-0118 exhibits immunomodulatory effects in inflammatory bowel disease (IBD) models.

BRD2 BD1:36.7 μM (Kd)

KB-0118 (1-10 μM, 12 hours) downregulates pro-inflammatory cytokines such as TNF, MIF, and CSF2 in PMA/Ionomycin-treated Jurkat cells. In RAW 264.7 cells treated with LPS, KB-0118 (1-10 μM, 12 hours) reduces cytokines like IL-1β, IL-6, IL-23a, and Cxcl11. The compound (5 μM, 5 days) inhibits proliferation of mouse CD4+ T cells activated by anti-CD3 and anti-CD28, demonstrated by reduced division, proliferation, expansion, and replication indices. Furthermore, KB-0118 (5 μM, 5 days) decreases the proportion of Th17 cells (RORγt+ IL-17A+), indicating inhibited differentiation, while increasing the proportion of Th2 cells (GATA-3+ IL-4+), suggesting enhanced Th2 polarization. Additionally, KB-0118 (0.01-1 μM, 24 hours) improves the viability of Caco-2 cells treated with DSS (5%, 48 hours).

KB-0118 (200 mg/kg, dissolved in drinking water for 7 days) alleviates colitis in a DSS (3% in drinking water) induced colitis model. Furthermore, KB-0118 (50 mg/kg, orally, once daily for a 6-week course) mitigates T-cell-mediated colitis by reducing IL-17a-driven inflammation in a chronic T-cell-mediated colitis model. KB-0118 (50-250 mg/kg, administered via gavage for 14 days) is well tolerated in both male and female C57BL/6 mice.