Treatment of liver fibrosis with oral hepatic stable and non-genotoxic HDAC inhibitors

Liver fibrosis/cirrhosis affects more than 100 million people worldwide and represents one of the most common causes of death in adults. Currently no effective pharmacotherapy is available for liver fibrosis. The only proven therapy is liver transplantation. Recent studies implicate that some isoforms of histone deacetylase (HDAC) play a role in development of liver fibrosis but all current HDAC inhibitors (HDACI) have major shortcomings (low HDAC isozyme selectivity, poor in vivo pharmacokinetics [PK], low solubility, and long-term safety concerns due to potential mutagenicity) that limit their utility in clinical treatment for fibrosis. Recently we identified a class of novel HDACI working through both allosteric and competitive mechanisms. The lead compounds in this class are more potent and have better PK properties, liver stable, and lower predicted toxicity profile than all current FDA-approved HDACI for cancer therapy. Moreover, we recently showed that lead compounds (LP-411 and LP-342) inhibit human hepatic stellate cell (HSC) activation and/or decrease liver fibrosis in mice. In clinic, a long-term oral administration is needed for fibrosis treatment. In this study, we aim to optimize LP-342 oral dosage formulation and deterrmine the therapeutic ranges and potential organ toxicity to determine if the new-generaton of liver stable HDACI can be used as an anti-fibrotic therapeutic for liver diseases. The final lead candidate will then be examined with authentic mouse CCl4 and bile duct ligation (BDL) models to determine preliminary efficacy against hepatic fibrosis. In Aim 1, we will optimize LP-342 aqueous solubility through conjugate salt formation. Aqueous solubility at pH 2.0/5.6, pharmacology, oral bioavailability, and maximal tolerated dose/organ toxicity of LP-342 will be characterized. We expect aim 1 will generate an aqueous oral formulation and determine the optimal administrate dose/frequency for aim 2. In Aim 2 we will determine the efficacy as a proof of concept study for the new lead HDACI candidate to prevent/treat fibrosis in vivo using most widely accepted mouse CCl4 and bile duct ligation models. We will examine the effects of the new lead candidate on liver injury, inflammation, HSC activation, liver fibrosis, and epigenetic regulation of gene expression related to inflammation and fibrosis after CCl4 and BDL. We will also elucidate whether LP-342 can be administered in later stage to block progress or even enhance resolution of fibrosis. Success of this study will identify a novel therapeutic strategy and develop much-needed, effective new drugs for delaying the progress and/or treatment of fibrosis, thus decreasing mortality and improving clinical outcomes in patients with chronic liver disease and cirrhosis.Project NarrativeOur goal is to develop novel histone deacetylase inhibitors (HDACI) with high potency and safety margin for therapy of liver fibrosis/cirrhosis, a disease that is one of the leading causes of death in adults. In this study, we will optimize LP-342 oral dosage formulation, determine its safe therapeutic margin, and charaterize its anti-fibrotic efficacy in mice to develop a much-needed, effective new antifibrotic drug that is suitable for clinical use to decrease mortality and improve clinical outcomes in patients with chronic liver disease and cirrhosis.