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

肝纤维化/肝硬变影响全球1亿多人，是全球最大的 成人常见死因。目前尚无有效的药物治疗肝纤维化。这个 唯一被证实的治疗方法是肝移植。最近的研究表明，组蛋白脱乙酰基酶的某些亚型 (HDAC)在肝纤维化的发展中起作用，但目前所有的HDAC抑制剂(HDACi)都有主要的 缺点(HDAC同工酶选择性低、体内药代动力学[PK]差、溶解度低和长期 潜在的致突变性的安全性问题)，限制了其在临床治疗纤维化方面的应用。最近我们 确定了一类通过变构和竞争机制发挥作用的新型HDACi。领头羊 这类化合物效力更强，具有更好的PK特性，肝脏稳定，预测的毒性较低 比目前FDA批准的所有用于癌症治疗的HDACi都要高。此外，我们最近展示了铅 化合物(LP-411和LP-342)抑制人肝星状细胞(HSC)激活和/或降低肝脏 小鼠的纤维化。在临床上，肝纤维化的治疗需要长期口服。在本研究中，我们的目标是 优化LP-342口服剂量处方，确定治疗范围和潜在器官 确定新一代肝脏稳定型HDACi是否可用作抗纤维化药物的毒性 治疗肝病。最终的领头羊候选人将用真正的鼠标CCl4进行检查 以及胆管结扎(BDL)模型，以确定其抗肝纤维化的初步疗效。在目标1中， 我们将通过形成共轭盐来优化LP-342的水溶解性能。在pH 2.0/5.6的水溶液中的溶解度， 将描述LP-342的药理作用、口服生物利用度和最大耐受量/器官毒性。 我们预计目标1号将产生一种水溶液口服配方并确定最佳给药方案 目标2的剂量/频率。在目标2中，我们将确定作为对新铅的概念研究的有效性 使用最广泛接受的小鼠CCL4和胆管结扎在体内预防/治疗纤维化的HDACi候选药物 模特们。我们将检查新的候选铅对肝脏损伤、炎症、HSC激活、肝脏 纤维化，以及CCl4和BDL后炎症和纤维化相关基因表达的表观遗传调节。 我们还将阐明LP-342是否可以在后期应用以阻止进展甚至增强 纤维化消退。这项研究的成功将确定一种新的治疗策略，并开发出急需的 有效的新药用于延缓纤维化的进展和/或治疗，从而降低死亡率和 改善慢性肝病和肝硬变患者的临床结局。

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.