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

肝缺血/再灌注损伤（IRI）发生在许多临床情况下，例如外伤、肝脏手术 （例如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 失败和死亡。它还会损害手术和创伤后的长期结果。目前，尚无有效 治疗可用于肝脏 IRI 的预防/治疗。最近我们鉴定了一类新的组蛋白 脱乙酰酶抑制剂（HDACI）通过变构和竞争机制发挥作用。领先 此类化合物更有效，具有更好的药代动力学 (PK) 特性和更低的预测值 毒性特征优于目前 FDA 批准的所有 HDACI。此外，我们最近证明了一种先导化合物 LP- 411，阻断线粒体功能障碍并减轻肝缺血再灌注后的肝损伤和炎症。在诊所里， IRI 需要肠外给药途径。因此，我们的目标是生成具有高水平的领先 HDACI 效力和选择性、低预测毒性以及通过修饰优化的肠外注射 PK LP-411的分子结构，从而产生一种新的HDACI，可以有效降低肝 IRI 在体内，适合临床使用。在目标1中，我们将通过优化结构生成新的HDACI 用于肠胃外给药的 LP-411。我们还将用 芳香杂环基团，并通过更具选择性的金属结合基团提高 HDAC 选择性，同时 保持几何、氢键和疏水相互作用。 HDAC 抑制的效力 将测试 HDAC 选择性以选择新的先导化合物。水溶性和预测的毒性，以及 将确定新先导化合物肠胃外注射的体内 PK 特性。我们期望这 研究将产生新的先导候选药物，它们具有更好的选择性、效力、溶解度和 PK 特性 与 LP-411 相比，肠胃外给药但预测毒性较低。目前的主要候选者 LP-411 显着减少肝 I/R 后的肝损伤和炎症，表明 HDAC 抑制是一种新颖的、 有效的治疗策略。因此，在目标 2 中，我们将确定功效作为概念研究的验证 使用广泛接受的小鼠 I/R 模型来预防/治疗体内肝脏 IRI 的新的主要 HDACI 候选药物。 确定最大耐受剂量后，我们将检查新的主要候选药物对 细胞死亡、转氨酶释放、肝功能、炎症和肝 I/R 后的存活。我们还将阐明 这些新型 HDACI 是否只能用于择期手术，还是既可以用于择期手术，又可以用于择期手术？ 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急需的有效药物 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.