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损伤，但自身也可能失调，对宿主造成有害后果。近年来，炎症细胞因子TNF-¿已被临床证实是几种炎症性疾病的主要驱动因素，并且生物制药药物已经上市，可以阻断TNF-¿的作用。然而，这些药物仅对一小部分患者有效，并可能导致严重甚至致命的副作用。此外，由于它们是重组蛋白，这些药物必须经肠给药，因此需要反复注射。对具有更好疗效/毒性的新型抗炎药物，特别是可口服的小分子药物的持续迫切需求。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TNF-转录因子的化合物，该因子是我们12年前在实验室克隆的，名为LITAF。筛选文库部分包括膳食补充剂和已建立的营养保健品，包含至少一类显示TNF-抑制活性的天然产物。特别是，从卡瓦根提取物中分离的几种化合物被发现在细胞分析中介导TNF-分泌的大量减少。此外，与对照动物相比，发现特定的卡瓦衍生化合物可以保护小鼠免受致死剂量的LPS或实验性牙周炎的伤害。重要的是，该系列中的一种代表性化合物被证明具有很好的药物特性，包括大鼠的口服生物利用度，并且初步的药物化学努力已经确定

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-¿ has been clinically validated as a primary driver of several inflammatory diseases, and biopharmaceutical drugs have been marketed that block TNF-¿ 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-¿ 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-¿ suppression activity. In particular, several compounds isolated from kava root extract were found to mediate substantial reduction of TNF-¿ 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.