Long Keith, Vaughn Zoe, McDaniels Michael David, Joyasawal Sipak, Przepiorski Aneta, Parasky Emily, Sander Veronika, Close David, Johnston Paul A, Davidson Alan J, de Caestecker Mark, Hukriede Neil A, Huryn Donna M
Department of Pharmaceutical Sciences, School of Pharmacy and Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand 1010.
ACS Pharmacol Transl Sci. 2022 Mar 16;5(4):207-215. doi: 10.1021/acsptsci.1c00243. eCollection 2022 Apr 8.
Acute kidney injury (AKI), a sudden loss of kidney function, is a common and serious condition for which there are no approved specific therapies. While there are multiple approaches to treat the underlying causes of AKI, no targets have been clinically validated. Here, we assessed a series of potent, selective competitive inhibitors of histone deacetylase 8 (HDAC8), a promising therapeutic target in an AKI setting. Using biochemical assays, zebrafish AKI phenotypic assays, and human kidney organoid assays, we show that selective HDAC8 inhibitors can lead to efficacy in increasingly stringent models. One of these, PCI-34051, was efficacious in a rodent model of AKI, further supporting the potential for HDAC8 inhibitors and, in particular, this scaffold as a therapeutic approach to AKI.
急性肾损伤（AKI）是一种肾功能的突然丧失，是一种常见且严重的病症，目前尚无经批准的特异性治疗方法。虽然有多种方法可治疗AKI的潜在病因，但尚无靶点得到临床验证。在此，我们评估了一系列组蛋白去乙酰化酶8（HDAC8）的强效、选择性竞争性抑制剂，HDAC8是AKI治疗中一个有前景的靶点。通过生化分析、斑马鱼AKI表型分析和人类肾类器官分析，我们表明选择性HDAC8抑制剂在越来越严格的模型中可产生疗效。其中一种抑制剂PCI-34051在AKI的啮齿动物模型中有效，进一步支持了HDAC8抑制剂，特别是这种骨架作为AKI治疗方法的潜力。
