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

Hepatic ischemia reperfusion injuryIRIoccurs in many clinical situationssuch as traumahepatic surgerye gliver resection for tumor treatmentliver donation and transplantationshock and vascular diseasesHepatic I R causes severe liver injury and promotes inflammationleading to liver dysfunctionmultiple organ failure and deathIt also compromises long term outcomes after surgery and traumaCurrentlyno effective therapy is available for hepatic IRI prevention treatmentRecently we identified a class of novel histone deacetylase inhibitorHDACIworking through both allosteric and competitive mechanismsThe lead compounds in this class are more potent and have better pharmacokinecticPKproperties and lower predicted toxicity profile than all current FDA approved HDACIMoreoverwe recently showed that a lead compoundLPblocks mitochondrial dysfunction and attenuates liver injury and inflammation after hepatic I RIn the clinica parenteral administered route is needed for IRIThusour goal is to generate a lead HDACI with high potency and selectivitylow predicted toxicityand optimized PK for parenteral injection by modification of the molecular structure of LPthus generating a new HDACI that can effectively decrease hepatic IRI in vivo and is suitable for clinical useIn Aimwe will generate new HDACI by optimizing the structure of LPfor parenteral administrationWe will also replace the potential toxicunsaturated ketone with aromatic heterocyclic groupsand improve HDAC selectivity with more selective metal binding groups while maintaining the geometrichydrogen bondingand hydrophobic interactionThe potency of HDAC inhibition and HDAC selectivity will be tested to select new lead compoundsAqueous solubility and predicted toxicityand in vivo PK properties for parenteral injection of the new lead compound will be determinedWe expect that this study will generate new lead candidates that have better selectivitypotencysolubilityand PK properties for parenteral administration but lower predicted toxicity compared to LPThe current lead candidate LPmarkedly decreases liver injury and inflammation after hepatic I Rsuggesting that HDAC inhibition is a noveleffective therapeutic strategyTherefore in Aimwe 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 modelAfter determination of the maximum tolerated dosagewe will examine the effects of the new lead candidate on cell deathtransaminase releaseliver functioninflammation and survival after hepatic I RWe 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 situationse gtraumaby comparing the efficacy of pre ischemic and post ischemic treatmentThe success of this study will identify a novel therapeutic strategy and develop much neededeffective new drugs for prevention treatment of hepatic IRIthus decreasing mortality and improving clinical outcomes in surgerytrauma and other diseases related to liver IRI Hepatic ischemia reperfusion occurs frequently in clinical settings and causes severe liver injuryleading to liver dysfunctionmultiple organ failure and deathOur goal is to develop a novel histone deacetylase inhibitorHDACIwith high potency and selectivitysuperior PK properties for parenteral injectionand low predicted toxicity risk by modification of the molecular structure of a current leading HDACI candidate LPthus generating a new HDACI that is suitable for clinical use to inhibit hepatic ischemia reperfusion injuryIRISuccess of this study will identify a novel therapeutic target and develop much neededeffective new drugs for prevention treatment of hepatic IRIthus decreasing mortality and improving clinical outcomes in surgerytraumashockand other diseases related to liver IRI