The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei 230032, China.
Clin Sci (Lond). 2019 Jul 25;133(14):1609-1627. doi: 10.1042/CS20190599. Print 2019 Jul 31.
Acute kidney injury (AKI) is a destructive clinical condition induced by multiple insults including ischemic reperfusion, nephrotoxic drugs and sepsis. It is characterized by a sudden decline in renal function, in addition to excessive inflammation, oxidative stress and programmed cell death of renal tubular epithelial cells. RIPK1-mediated necroptosis plays an important role in AKI. In the present study, we evaluated the treatment effects of Compound-71 (Cpd-71), a novel RIPK1 inhibitor, by comparing with Necrostatin-1 (Nec-1), a classic RIPK1 inhibitor, which has several drawbacks like the narrow structure-activity relationship (SAR) profile, moderate potency and non-ideal pharmacokinetic properties, and Our results showed that pretreatment of Cpd-71 attenuated cisplatin-induced renal injury, restored renal function and suppressed renal inflammation, oxidative stress and cell necroptosis. In addition, Cpd-71 inhibited renal damage while reducing the up-regulated serum creatinine (Cr) and blood urea nitrogen (BUN) levels in established AKI mice model. Consistently, we confirmed that Cpd-71 exhibited more effectively suppressive effect on cisplatin-induced renal tubular cell necroptosis than Nec-1, by physically binding to the allosteric type III ligand binding site of RIPK1, thereby reduced RIPK1 kinase activity, RIPK1/RIPK3 complex formation and phosphor-MLKL membrane translocation by molecular docking, Western blot, co-immunoprecipitation and cellular thermal shift assay (CETSA). Taken together, we currently showed that targeting RIPK1 with Cpd-71 may serve as a promising clinical candidate for AKI treatment.
急性肾损伤（AKI）是由多种损伤引起的破坏性临床病症，包括缺血再灌注、肾毒性药物和脓毒症。其特征是肾功能突然下降，此外还伴有过度炎症、氧化应激和肾小管上皮细胞程序性细胞死亡。RIPK1 介导的坏死性凋亡在 AKI 中起重要作用。在本研究中，我们通过比较新型 RIPK1 抑制剂 Compound-71（Cpd-71）与经典 RIPK1 抑制剂 Necrostatin-1（Nec-1）的治疗效果，评估了 Cpd-71 的治疗效果，Nec-1 具有结构-活性关系（SAR）谱狭窄、效力中等和不理想的药代动力学特性等缺点。我们的结果表明，Cpd-71 预处理可减轻顺铂诱导的肾损伤，恢复肾功能并抑制肾炎症、氧化应激和细胞坏死性凋亡。此外，Cpd-71 抑制肾损伤的同时降低了已建立的 AKI 小鼠模型中上调的血清肌酐（Cr）和血尿素氮（BUN）水平。一致地，我们通过分子对接、Western blot、共免疫沉淀和细胞热转移分析（CETSA）证实，Cpd-71 比 Nec-1 更有效地抑制顺铂诱导的肾小管细胞坏死性凋亡，通过与 RIPK1 的变构型 III 配体结合位点物理结合，从而降低 RIPK1 激酶活性、RIPK1/RIPK3 复合物形成和磷-MLKL 膜易位。综上所述，我们目前表明，用 Cpd-71 靶向 RIPK1 可能成为 AKI 治疗的有前途的临床候选药物。
