Role of LITAF in Inflammatory Disease

描述(由申请人提供)：炎症反应保护身体免受感染和伤害，但本身可能变得调节失调，对宿主造成有害后果。近年来，炎性细胞因子肿瘤坏死因子-α已被临床证实是几种炎症性疾病的主要驱动力，并已上市了阻断肿瘤坏死因子-α作用的生物药物。然而，这些药物只对一小部分患者有效，可能会导致严重的副作用，甚至致命的副作用。此外，因为它们是重组蛋白质，这些药物必须经肠道给药，因此需要重复注射。仍然迫切需要具有改善疗效/毒性的新型抗炎药物，特别是可以口服的小分子药物。我们最近筛选了一个小分子化合物文库，试图识别能够干扰我们12年前在实验室克隆的一种名为LITAF的肿瘤坏死因子-α转录因子的化合物。筛选文库部分包括膳食补充剂和已建立的营养食品，包含至少一类显示肿瘤坏死因子-α抑制活性的天然产品。特别是，从卡瓦根萃取物中分离出的几种化合物在细胞实验中被发现能显著减少肿瘤坏死因子-α的分泌。此外，与对照动物相比，发现特定的kava衍生化合物可以保护小鼠免受致命剂量的内毒素或实验性牙周炎的影响。重要的是，该系列中的一种具有代表性的化合物被证明具有良好的药学性能，包括在老鼠身上的口服生物利用度，初步的药物化学工作已经确定了该分子上可以修饰的区域，以优化该化合物的性能。我们总体研究计划的一个关键目标是确定Kava化合物产生生物学效应的分子靶点(S)，并阐明它们的作用机制。然而，必须提高化合物的效力才能实现这些目标。本申请概述了3个目标：首先，将采用全面的药物化学方法来设计、合成和测试化合物，目标是提供2-3个经过生物化学良好表征和验证的工具化合物，以优化效力和体内暴露。其次，这些经过优化的Kava衍生化合物将在动物炎症模型中进行测试，以在体内验证它们的目标识别和作用机制研究，并确定它们作为一类新的抗炎药的潜力。第三，确定Kava化合物介导LITAF抑制内毒素诱导的细胞因子分泌的信号转导途径中的分子靶点(S)。我们的目标是阐明优化的卡瓦化合物的作用机制，朝着识别适合临床开发的新型抗炎化合物迈出一步。

DESCRIPTION (provided by applicant): The inflammatory response protects the body against infection and injury but can itself become dysregulated with deleterious consequences to the host. In recent years the inflammatory cytokine TNF-α has been clinically validated as a primary driver of several inflammatory diseases, and biopharmaceutical drugs have been marketed that block TNF-α action. These drugs, however, are effective in only a subset of patients, and can cause severe and even fatal side effects. Moreover, because they are recombinant proteins these drugs must be administered perenterally, thus requiring repeated injections. There is a continued critical need for novel anti-inflammatory drugs that possess improved efficacy/toxicity profiles, and in particular for small molecule drugs that can be taken orally. We have recently screened a small molecule compound library in an attempt to identify compounds capable of interfering with a TNF-α transcription factor that we cloned in our laboratory 12 years ago named LITAF. The screening library, comprising in part dietary supplements and established nutraceuticals, contained at least one class of natural products that displayed TNF-α suppression activity. In particular, several compounds isolated from kava root extract were found to mediate substantial reduction of TNF-α secretion in a cellular assay. Moreover, specific kava-derived compounds were found to protect mice against lethal doses of LPS or experimental periodontitis, compared to control animals. Importantly, a representative compound from this series was shown to possess promising pharmaceutical properties including oral bioavailability in rats, and a preliminary medicinal chemistry effort has identified regions on the molecule that can be modified to optimize the compound's properties. A key objective of our over-arching research program is to identify the molecular target(s) by which kava compounds elicit their biological effect, and to elucidate their mechanism of action. However the potency of the compounds must be improved to enable these goals. The present application outlines 3 Aims: First, a comprehensive medicinal chemistry approach will be taken to design, synthesize and test compounds with the goal of delivering 2-3 biochemically well- characterized and validated tool compounds optimized for potency and for in vivo exposure. Second, these optimized, kava-derived compounds will be tested in animal models of inflammation to validate them in vivo for target identification and mechanism of action studies, and to establish their potential as a new class of anti-inflammatory drugs. Third to determine the molecular target(s) in the signal transduction pathway by which kava compounds mediate LITAF inhibition of LPS-induced cytokine secretion. Our goal is the elucidation of the mechanism of action of optimized kava compounds, a step towards identifying novel anti-inflammatory compounds suitable for clinical development.