Small Molecule Erythropoietin Receptor Agonists for the Treatment of Acute Kidney

描述(申请人提供)：急性肾损伤(AKI)导致肾功能突然受损。AKI的影响可能是暂时的，随后完全或部分恢复，但通常会进展为更严重的肾功能不全或终末期肾脏疾病。目前还没有得到批准的治疗方法。以前的研究支持这样的观点，即在足够高的剂量下，重组人(Rh)促红细胞生成素(EPO)对AKI动物模型的肾脏具有保护作用。然而，在临床前研究中，需要高剂量的药物来实现肾脏保护，每天5000IU/kg，因为重组人促红细胞生成素不能有效地进入血管外系统。目前在临床环境中推荐的重组人促红细胞生成素剂量要低得多(每周最高可达900IU/kg)，这表明在提供肾脏保护所需的水平上使用重组人促红细胞生成素在治疗上是不可行的。与这一理念一致的是，第一批检测重组人促红细胞生成素在AK中的临床研究提供了混合的结果，支持了需要更有效的治疗的结论。重组人促红细胞生成素还具有促红细胞生成活性，会增加血栓事件的风险，因此也会产生不良反应。STATegics专注于小分子细胞因子模拟物的发现和开发，并已发现具有强大组织保护活性的非红细胞生成性EPO受体(EPOR)激动剂。使用人近端小管细胞系HK-2，我们发现这些化合物激活了EPOR，并提高了体外培养的肾细胞的存活率。此外，我们的研究表明，这些化合物对体内化学诱导的AKI后的肾功能具有保护作用。在大鼠和人类神经元中也观察到了强大的细胞保护作用，说明了这些小分子对细胞毒攻击的广泛保护作用。体外安全性评估没有发现任何安全问题或靶外效应，在体内初步耐受性研究中，这些化合物的耐受性很好。重要的是，在体外或体内，没有观察到细胞保护性浓度下的红细胞生成活性，这表明与重组人促红细胞生成素相比，体内血栓事件的风险降低。这一第一阶段计划旨在建立一种组织保护性、非促红细胞生成素小分子促红细胞生成素EPOR激动剂的概念验证，作为治疗AKI的潜在疾病改良剂。本研究的目的是利用体外原代培养的人和大鼠肾细胞，对该系列中两个有希望的化合物的保护作用进行评估和分级，并在体内测试最有希望的化合物对顺铂诱导的AKI大鼠的保护作用。如果该化合物的肾脏保护作用得到证实，我们的目标将是扩展到更多的肾脏损伤模型，如缺血-再灌注模型。后一项研究将是未来第二阶段应用的主题，其中还将包括对化合物在体外和体内的安全性进行更彻底的评估。我们的长期目标是将先导化合物推进到治疗AKI的临床试验中。

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) leads to a sudden impairment of renal function. The effects of AKI may be transient followed by full or partial recovery, but often progress to more severe renal insufficiency or end-stage renal disease. There are no approved therapies available. Previous studies support the view that, at sufficiently high doses, recombinant human (rh) erythropoietin (EPO) protects kidneys in animal models of AKI. However, high doses are needed to achieve renal protection in preclinical studies, 5,000 IU/kg daily, because rhEPO does not efficiently access the extravascular system. The currently recommended doses of rhEPO in clinical settings are far lower (maximum to 900 IU/kg weekly), suggesting that dosing rhEPO at levels required to provide renal protection are not therapeutically viable. Consistent with this notion, the first clinical studies testing rhEPO in AK have provided mixed results, supporting the conclusion that more effective therapies are needed. RhEPO also associates with adverse effects due to its erythropoietic activity increasing the risk of thrombotic events. STATegics is focused on the discovery and development of small molecule cytokine mimetics and has identified non-erythropoietic EPO receptor (EPOR) agonists with potent tissue-protective activity. Using the human proximal tubule cell line HK-2, we find that these compounds activate EPOR and improve survival of the kidney cells in vitro. In addition, our studies indicate protective effects of the compounds on kidney function following chemically-induced AKI in vivo. Potent cytoprotective effects were also observed in rat and human neurons, illustrating broadly protective effects of these small molecules against cytotoxic challenges. In vitro safety assessment did not identify any safety concerns or off-target effects, and the compounds were well tolerated in an initial tolerability study in vivo. Importantly, no erythropoietic activity was observed at cytoprotective concentrations, in vitro or in vivo, suggesting a reduced risk of thrombotic events in vivo when compared to rhEPO. This Phase I program aims to establish a proof-of-concept for tissue- protective, non-erythropoietic small molecule erythropoietin EPOR agonists as potential disease-modifying agents in the treatment of AKI. The aim of the proposed studies is to evaluate and rank the protective effects of two promising compounds in this series using primary human and rat kidney cells in vitro and to test the ability of the most promising compound to protect rats from cisplatin-induced AKI in vivo. If the compound's kidney protective effects can be confirmed, our aim will be to expand into additional models of kidney injury, such as ischemia-reperfusion models. The latter studies would be the subject of a future Phase II application, which would also include more thorough assessment of the compounds' safety in vitro and in vivo. Our long- term goal is to advance the lead compound into clinical testing for the treatment of AKI.