ZL0590 is a potent, orally active, BRD4 BD1-selective inhibitor with IC50 of 90 nM for human BRD4 BD1. ZL0590 inhibits Poly(I:C)-induced expression of inflammatory genes CIG5 and IL-6 in hSAECs with IC50 of 0.2 and 0.37 uM, respectively. ZL0590 is 10-fold more selective over BRD4 BD2, BRD2 BD1, and BRD2 BD2, highly selective over other BET members (e.g., BRD3 and BRDT) and non-BET protein (e.g., CBP). ZL0590 binds selectively to WT BRD4-BD1 but not WT BRD4-BD2 nor E151-mutated BRD4-BD1. ZL0590 (10 mg/kg, po) blocked poly(I:C)-induced acute airway inflammation in mice.
