ZL0969 is a potent, selective, and orally bioavailable BRD4 inhibitor with IC50 of 82 nM and 87 nM for BRD4 BD1 and BRD4 BD2, respectively.
ZL0969 showed >10-fold binding selectivity for BRD4 BDs over other BET-family BDs, showed no detectable binding for the non-BET CBP BD.
ZL0969 displays a strong inhibitory activity on IL-6 (IC50=0.253 ± 0.034 µM), CIG5 (IC50 = 0.270 ± 0.023 µM), IL-8 (IC50 = 0.234 ± 0.032 µM), and ISG54 (IC50 = 0.242 ± 0.027 µM) gene expression in small airway epithelial cells (hSAECs).
ZL0969 disrupts epithelial mesenchymal transition (EMT).
ZL0969 (20 mg/kg) treatment via oral gavage reduced myofibroblast formation and deposition of denatured ECM (collagen and laminin a1) in the alveolar space and improved disease scores in in bleomycin-induced fibrosis mice model.
ZL0969 reduced a pathogenic population of alveolar progenitor cells expressing integrin (ITG)-A6/B4, tumor related protein 63 (Trp63) and keratin (Krt).