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，如创伤，肝脏手术

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.