Next generation HDAC inhibitors with superior potency, selectivity, and pharmacokinetic profiles for the treatment of liver ischemia-reperfusion injury

肝脏缺血再灌注损伤(IRI)广泛存在于创伤、肝脏手术等临床情况中 (例如，用于治疗肿瘤的肝切除、肝脏捐赠和移植)、休克和血管疾病。 肝脏I/R导致严重的肝脏损伤和促进炎症，导致肝功能障碍，多器官 失败和死亡。它还会影响手术和创伤后的长期结果。目前，没有有效的 治疗可用于肝脏IRI的预防/治疗。最近我们发现了一类新的组蛋白 脱乙酰酶抑制剂(HDACi)通过变构和竞争机制发挥作用。领头羊 这类化合物效力更强，具有更好的药动学(PK)特性和较低的预测值 毒性比目前所有FDA批准的HDACi都要高。此外，我们最近发现一种先导化合物Lp- 411，阻断线粒体功能障碍，减轻肝I/R后肝损伤和炎症。 IRI需要肠外给药途径。因此，我们的目标是产生具有高性能的领先HDACi 静脉注射的效力和选择性、低预测毒性和优化的PK Lp-411的分子结构，从而产生一种新的HDACi，可以有效降低肝脏 体内存在IRI，适合临床使用。在目标1中，我们将通过优化结构来生成新的HDACi 静脉注射LP-411。我们还将用以下物质取代可能有毒的α，β-不饱和酮 芳香杂环基团，并通过更多选择性的金属结合基团提高HDAC的选择性 保持几何、氢键和疏水相互作用。HDAC抑制的效力和 将测试HDAC的选择性，以选择新的先导化合物。水的溶解度和预测的毒性，以及 将确定用于注射新的先导化合物的体内PK特性。我们预计这一次 研究将产生具有更好的选择性、效力、溶解性和PK属性的新的候选铅 肠外给药，但与LP-411相比，预期毒性较低。目前领先的候选人LP-411 显著减轻肝I/R后的肝损伤和炎症反应，提示HDAC抑制是一种新的， 有效的治疗策略。因此，在目标2中，我们将确定有效性作为概念研究的证据 利用被广泛接受的小鼠I/R模型，在活体内预防/治疗肝脏IRI的新的HDACi候选先导。 在确定了最大耐受剂量后，我们将检查新的铅候选人对 肝I/R后细胞死亡、转氨酶释放、肝功能、炎症和存活。我们还将阐明 无论这些新型的HDACi是只能用于择期手术，还是既可用于择期手术，又可用于 通过比较缺血前和缺血后的疗效来预测不可预测的急性情况(例如，创伤) 治疗。这项研究的成功将确定一种新的治疗策略，并开发出急需的、有效的 预防/治疗肝脏IRI的新药，从而降低死亡率和改善临床结果 手术、创伤和其他与肝脏IRI相关的疾病。

Hepatic ischemia/reperfusion injury (IRI) occurs in many clinical situations, such as trauma, hepatic surgery (e.g. liver resection for tumor treatment, liver donation and transplantation), shock and vascular diseases. Hepatic I/R causes severe liver injury and promotes inflammation, leading to liver dysfunction, multiple organ failure and death. It also compromises long-term outcomes after surgery and trauma. Currently, no effective therapy is available for hepatic IRI prevention/treatment. Recently we identified a class of novel histone deacetylase inhibitor (HDACI) working through both allosteric and competitive mechanisms. The lead compounds in this class are more potent and have better pharmacokinectic (PK) properties and lower predicted toxicity profile than all current FDA-approved HDACI. Moreover, we recently showed that a lead compound, LP- 411, blocks mitochondrial dysfunction and attenuates liver injury and inflammation after hepatic I/R. In the clinic, a parenteral administered route is needed for IRI. Thus, our goal is to generate a lead HDACI with high potency and selectivity, low predicted toxicity, and optimized PK for parenteral injection by modification of the molecular structure of LP-411, thus generating a new HDACI that can effectively decrease hepatic IRI in vivo and is suitable for clinical use. In Aim 1, we will generate new HDACI by optimizing the structure of LP-411 for parenteral administration. We will also replace the potential toxic α,β-unsaturated ketone with aromatic heterocyclic groups, and improve HDAC selectivity with more selective metal-binding groups while maintaining the geometric, hydrogen bonding, and hydrophobic interaction. The potency of HDAC inhibition and HDAC selectivity will be tested to select new lead compounds. Aqueous solubility and predicted toxicity, and in vivo PK properties for parenteral injection of the new lead compound will be determined. We expect that this study will generate new lead candidates that have better selectivity, potency, solubility, and PK properties for parenteral administration but lower predicted toxicity compared to LP-411. The current lead candidate LP-411 markedly decreases liver injury and inflammation after hepatic I/R, suggesting that HDAC inhibition is a novel, effective therapeutic strategy. Therefore in Aim 2, we will determine the efficacy as a proof of concept study for the new lead HDACI candidate to prevent/treat hepatic IRI in vivo using a widely accepted mouse I/R model. After determination of the maximum tolerated dosage, we will examine the effects of the new lead candidate on cell death, transaminase release, liver function, inflammation and survival after hepatic I/R. We will also elucidate whether these novel HDACI can be used only in elective surgery or can be used in both elective surgery and unpredictable acute situations (e.g., trauma) by comparing the efficacy of pre-ischemic and post-ischemic treatment. The success of this study will identify a novel therapeutic strategy and develop much-needed, effective new drugs for prevention/treatment of hepatic IRI, thus decreasing mortality and improving clinical outcomes in surgery, trauma and other diseases related to liver IRI.