Discovery of indol-6-yl-pyrrolo[2,3-c]pyridin-7-one derivatives as bromodomain-containing protein 4 (BRD4) inhibitors for the treatment of kidney fibrosis

Abstract

Uncovering new therapeutics for kidney fibrosis hold promise for chronic kidney disease (CKD). Considerable studies confirmed that BRD4 inhibition ameliorated kidney injury and fibrosis. In the study, we synthesized a series of indol-6-yl-pyrrolo[2,3-c]pyridin-7-one derivatives and biologically evaluated against BRD4 for structure-activity relationship (SAR). Notably, compound 3r (ZLD2218) exhibited the most potent inhibitory activity against BRD4, with the IC50 value of 107 nM, which was comparative to 92 nM of positive control JQ-1. Importantly, at the dose of 15 and 30 mg/kg/d for consecutive 8 days, ZLD2218 alleviated kidney injury and fibrosis in unilateral ureteral obstruction (UUO) mice, with the 30 mg/kg/d being competitive to 100 mg/kd/d of JQ1. Mechanically, ZLD2218 inhibited BRD4 expression and further suppressed fibrotic signaling in the kidneys of UUO mice and TGF-β1-stimulated TCMK-1 cells. Furthermore, ZLD2218 at the dose of 30 mg/kg/d for 8 days to C57BL/6J mice did not affect liver, kidney function and organ pathological changes. Collectively, compound 3r (ZLD2218) might be a promising lead compound of BRD4 inhibitor for the treatment of kidney fibrosis.