Development of Novel LANCL2-based Anti-diabetic Compounds

描述（由申请人提供）：大约2830万美国人患有II型糖尿病（T2D），超过40.1%的中年人患有前驱糖尿病，这是一种以糖耐量受损和胰岛素抵抗为特征的疾病。目前的抗糖尿病药物在改善胰岛素敏感性方面是有效的，但长期服用会产生显著的副作用，如心血管并发症、肝毒性、脂肪组织堆积、液体潴留、膀胱肿瘤等。我们已经发现了一种天然存在的类异戊二烯，脱落酸（ABA），它可以增加胰岛素敏感性，抑制超重和肥胖的炎症。最近，我们已经确定了LANCL2作为ABA的一个新的分子靶点。本项目将评估新型ABA衍生物治疗糖尿病的有效性和安全性。STTR I期的具体目标是：(1)生成20种ABA衍生物和类似物，用于开发糖尿病和肥胖相关炎症药物；(2)进行硅和体外筛选，以选择进一步开发的铅衍生物；(3)比较aba衍生药物对吡格列酮（已获批的糖尿病药物）在两种糖尿病小鼠模型中的口服疗效。在这项工作的最后，我们的团队将鉴定出两种ABA衍生物，它们经过了广泛的体外测试，是安全的，并且在两种糖尿病小鼠模型中被证明有效。我们将至少提交一项专利申请，其中包含针对LANCL2途径的新型抗糖尿病药物的强大物质组成要求。这些研究将区分ABA及其新衍生物的作用模式（MOA）与过氧化物酶体增殖激活受体g的结合。这项工作将为开发基于ABA的新型糖尿病治疗方法的可行性提供良好的评估。STTR II期将优化两种在糖尿病小鼠模型中已证明有效的先导化合物，并沿着调控途径推进它们，包括功效、作用方式、吸收、分布、代谢和排泄、药代动力学/药效学、毒代动力学分析和毒性评估，以完成提交研究性新药申请所需的测试，为人体临床试验做准备。为了优化口服给药，我们将在指南范围内开发更多具有分子性质（ClogP、分子量、极性表面积、环数、可旋转键、N和O原子、氢键供体和受体）的类似物；测试它们的功效和安全性。长期目标：生物疗法（BTI）技术的目标将是提供一种替代现有糖尿病治疗的口服治疗方法，成本更低，疗效更好，副作用更少。这项技术将解决糖尿病患者的健康问题，并将为美国每年仅处方药费用就超过125亿美元的2830万市场提供巨大的商业化潜力。

DESCRIPTION (provided by applicant): About 28.3 million Americans have type II diabetes (T2D) and over 40.1% of middle-aged adults have prediabetes, a condition characterized by impaired glucose tolerance and insulin resistance. Current antidiabetic medications are effective in improving insulin sensitivity, but their chronic administration has significant side effects suc as cardiovascular complications, hepatotoxicity, adipose tissue accumulation, and fluid retention, bladder tumors. We have discovered a naturally occurring isoprenoid, abscisic acid (ABA) that increases insulin sensitivity and suppresses inflammation in overweight and obesity. Recently, we have identified Lanthionine Synthetase Component C-Like 2 (LANCL2) as a novel molecular target for ABA. This project will evaluate the efficacy and safety of novel ABA derivatives for treating diabetes. The specific aims for the proposed STTR Phase I are: (1) To generate 20 derivatives and analogs of ABA for development of diabetes and obesity-related inflammation drugs; (2) To perform in silico and in vitro screening to select lead derivatives for further development; and (3) To compare the oral efficacy of ABA-derived drugs against pioglitazone, an approved diabetes drug, in two mouse models of diabetes. At the conclusion of this effort our team will have identified two derivatives of ABA that have undergone extensive in vitro testing and are safe and with proven efficacy in two mouse models of diabetes. We will have filed at least one patent application with robust composition of matter claims for the new class of anti-diabetic drugs that target the LANCL2 pathway. The proposed studies will differentiate the mode of action (MOA) of ABA and its new derivatives from binding to peroxisome proliferator-activated receptor g. This work will provide an excellent assessment of the feasibility of developing novel ABA-based treatments for diabetes. STTR Phase II will optimize two of the lead compounds with demonstrated efficacy in mouse models of diabetes and advance them along the regulatory pathway, including efficacy, mode of action, absorption, distribution, metabolism and excretion, phamacokinetics/pharmacodynamics, toxicokinetics analysis and toxicity assessment working towards the testing required to submit an investigational new drug application in preparation for human clinical trials. To optimize oral drug delivery we shall develop more analogs that have molecular properties (ClogP, molecular weight, polar surface area, numbers of rings, rotable bonds, N and O atoms, hydrogen bond donors and acceptors) within the guidelines; and test their efficacy and safety. Long Term Goal: The goal of BioTherapeutics (BTI) technology will be to provide an oral therapeutic alternative to existing diabetes treatments that costs less and provides greater efficacy with reduced adverse side effects. The technology will address the overlying health problem with patients suffering with diabetes and will provide a significant commercialization potential to a market of 28.3 million estimated to be over $12.5 Billion for prescription medication costs alone annually in the US.