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.

发现肾纤维化的新疗法为慢性肾病 (CKD) 带来了希望。大量研究证实，BRD4 抑制可改善肾损伤和纤维化。在这项研究中，我们合成了一系列 indol-6-yl-pyrrolo[2,3- c ]pyridin-7-one 衍生物，并对 BRD4 的构效关系 (SAR) 进行了生物学评估。值得注意的是，化合物3r (ZLD2218) 对 BRD4 表现出最有效的抑制活性，IC ₅₀值为 107 nM，与阳性对照 JQ-1 的 92 nM 相当。重要的是，在 15 和 30 mg/kg/d 连续 8 天的剂量下，ZLD2218 减轻了单侧输尿管梗阻 (UUO) 小鼠的肾损伤和纤维化，30 mg/kg/d 与 100 mg/kd/ JQ1的d。机械地，ZLD2218 抑制 BRD4 表达并进一步抑制 UUO 小鼠和 TGF-β1 刺激的 TCMK-1 细胞肾脏中的纤维化信号传导。此外，对C57BL/6J小鼠给予ZLD2218 30 mg/kg/d 8天，对肝、肾功能及器官病理变化均无影响。总的来说，化合物3r (ZLD2218) 可能是治疗肾纤维化的一种有前途的 BRD4 抑制剂先导化合物。