Kidney Research Institute, National Clinical Research Center for Geriatrics and Division of Nephrology, West China Hospital of Sichuan University, Chengdu, 610041, China.
Laboratory of Anesthesia & Critical Care Medicine, Translational Neuroscience Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
Eur J Med Chem. 2022 Mar 5;231:114153. doi: 10.1016/j.ejmech.2022.114153. Epub 2022 Feb 2.
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 IC 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.
发现治疗肾脏纤维化的新疗法为慢性肾脏病（CKD）带来了希望。大量研究证实 BRD4 抑制可改善肾脏损伤和纤维化。在这项研究中，我们合成了一系列吲哚-6-基-吡咯并[2,3-c]吡啶-7-酮衍生物，并对其进行了针对 BRD4 的结构活性关系（SAR）的生物学评估。值得注意的是，化合物 3r（ZLD2218）对 BRD4 表现出最强的抑制活性，IC 值为 107 nM，与阳性对照 JQ-1 的 92 nM 相当。重要的是，在连续 8 天每天 15 和 30 mg/kg/d 的剂量下，ZLD2218 减轻了单侧输尿管梗阻（UUO）小鼠的肾脏损伤和纤维化，30 mg/kg/d 的效果与 100 mg/kg/d 的 JQ1 相当。在机制上，ZLD2218 抑制 BRD4 表达，并进一步抑制 UUO 小鼠肾脏和 TGF-β1 刺激的 TCMK-1 细胞中的纤维化信号。此外，在连续 8 天给予 30 mg/kg/d 的剂量，ZLD2218 对 C57BL/6J 小鼠的肝脏、肾脏功能和器官病理变化没有影响。总之，化合物 3r（ZLD2218）可能是一种有前途的 BRD4 抑制剂先导化合物，可用于治疗肾脏纤维化。
