Targeting C/EBP-beta Phosphorylation for the Treatment of Lung Fibrosis

 描述（由申请人提供）：肺肌成纤维细胞（LMF）的活化是所有原因的慢性肺病中肺纤维化发展的原因，值得注意的是，通过细胞凋亡清除LMF可预防肺纤维化和肺损伤的发展，并可能允许从肺纤维化逆转中恢复。组织纤维化专家完全同意，抑制或逆转肌成纤维细胞活化（治疗靶点）对于肺纤维化的治疗至关重要。正如我们在我们的临床前研究中所记录的，尽管持续肺损伤，但两者都可以预防肺纤维化的进展以及可能的肺纤维化的消退。 研究，被认为是特发性肺纤维化（IPF）患者的重要临床靶点。最后，阻断肺纤维化的进展可能会减少肺癌的发展。我们研发的基础是开发新型“人源化”类肽（以前未报道）。我们使用模拟合成创建了一个库，以改善人类治疗的潜在陷阱。我们已经以逐步的方式进行了测定以选择最安全和最有效的“人源化”类肽（包括活化的原代人肌成纤维细胞中的凋亡测定;无细胞半胱天冬酶8活化测定;肺损伤/纤维化模型;小鼠中的初步毒理学测定）。我们已经在动物模型中开发了新型高效的抗纤维化类肽，在最先进的T细胞测定中没有免疫原性的证据，并且在小鼠微粒体系统和小鼠血液中具有出色的稳定性。所述铅类肽在水中具有优异的溶解性。这些功能应便于管理 在临床试验期间，通过吸入增加LMF的生物利用度。所提出的化合物显著抑制培养物中人和小鼠肌成纤维细胞的活化。这些化合物在初步毒理学研究（包括先导毒理基因组学）中对小鼠无毒，至少为治疗剂量的100倍。本1期STTR的拟定目标为：具体目标1：类肽先导物在肺纤维化小鼠模型中的疗效。具体目标2：小鼠中的药代动力学（单次和多次给药）以及人肺微粒体和人血浆中的体外稳定性试验。目前尚无治疗IPF肺纤维化的药物。完成拟定化合物的这些任务将使我们能够在IPF患者中进行II期STTR和临床开发。

 DESCRIPTION (provided by applicant): Activation of lung myofibroblasts (LMF) is responsible for the development of lung fibrosis in chronic lung diseases of all causes and remarkably, LMF clearance by apoptosis may prevent development of lung fibrosis and lung injury, and possibly allow recovery from reversal of lung fibrosis. There is full agreement among tissue fibrosis experts that inhibiting o reversing myofibroblast activation (the therapeutic target) is critical fr the treatment of lung fibrosis. Both preventing progression of lung fibrosis as well as possibly, regression of lung fibrosis in spite of continued lung injury, as we documented in our pre-clinical studies, are considered important clinical targets for patients with Idiopathic Pulmonary Fibrosis (IPF). Finally, blocking the progression of lung fibrosis may decrease development of lung cancer. The basis for our Research and Development is the development of novel 'humanized' peptoids (not previously reported). We created a library using analog synthesis to improve potential pitfalls for human therapy. We have performed in a step-wise manner assays to select the safest and most efficient 'humanized' peptoids (including apoptosis assays in activated primary human myofibroblasts; cell-free caspase 8 activation assays; lung injury/fibrogenesis models; preliminary toxicology assays in mice). We have developed novel and highly effective anti-fibrotic peptoids in animal models, with no evidences of immunogenicity in state-of-the-art T-cell assays and with exceptional stability in mouse microsomal systems and mouse blood. The lead peptoid has excellent solubility in water. These features should facilitate administration by inhalation with increased bioavailability to the LMF during clinical trials. The proposed compounds markedly inhibit activation of human and mouse myofibroblast in culture. These compounds were not toxic in the preliminary toxicology studies, including pilot toxicogenomics, to mice at least at 100-fold the therapeutic dose. The aims that are proposed for this Phase-1 STTR are: Specific Aim 1: Efficacy of the Lead Peptoid in Lung Fibrosis Mouse Models. Specific Aim 2: Pharmacokinetics (Single and Multiple doses) in Mice and Stability Assays in vitro in Human Lung Microsomes and Human Plasma. There is no medication for the treatment of lung fibrosis in IPF. Completion of these tasks for the proposed compounds will allow us proceeding with a Phase-2 STTR and clinical development in patients with IPF.