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）发生于多种临床情况，如创伤、肝脏手术等 (e.g.用于肿瘤治疗的肝切除术、肝脏捐献和移植）、休克和血管疾病。 肝脏I/R导致严重的肝损伤并促进炎症，导致肝功能障碍、多器官功能障碍、肝硬化 失败和死亡。它还损害了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起作用。率先 这类化合物更有效，具有更好的药代动力学（PK）特性和更低的预测值。 比目前FDA批准的所有HDACI的毒性更强。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并减轻肝I/R后的肝损伤和炎症。在诊所里， IRI需要肠胃外给药途径。因此，我们的目标是产生一个领先的HDACI与高 效价和选择性，预测毒性低，通过修饰优化了胃肠外注射的PK LP-411的分子结构，从而产生一种新的HDACI， IRI在体内，适合于临床使用。在目标1中，我们将通过优化结构来产生新的HDACI LP-411用于肠胃外给药。我们还将用α，β-不饱和酮替代潜在的有毒物质， 芳族杂环基团，并且用更有选择性的金属结合基团改善HDAC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选择性以选择新的先导化合物。水溶性和预测毒性，以及 将测定新的先导化合物的肠胃外注射的体内PK特性。我们期望这 研究将产生新的先导候选物，其具有更好的选择性、效力、溶解性和PK特性， 肠胃外给药，但与LP-411相比预测毒性较低。目前的主要候选人LP-411 显著减少肝I/R后的肝损伤和炎症，表明HDAC抑制是一种新的， 有效的治疗策略。因此，在目标2中，我们将确定疗效，作为概念验证研究， 使用广泛接受的小鼠I/R模型在体内预防/治疗肝脏IRI的新的主要HDACI候选物。 在确定最大耐受剂量后，我们将检查新的先导候选药物对以下方面的影响： 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 这些新的HDACI是否可以仅用于选择性手术或既可以用于选择性手术， 不可预测的紧急情况（例如，通过比较缺血前和缺血后的疗效 治疗这项研究的成功将确定一种新的治疗策略，并开发急需的，有效的 用于预防/治疗肝脏IRI的新药，从而降低死亡率并改善临床结局， 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.