Design & Discovery of Novel Antimetastatic MMP Inhibitor

描述(由申请人提供)： 宿主生物基质蛋白降解引起的肿瘤转移扩散 仍然是癌症治愈的最大障碍。两个关键矩阵-降级 金属蛋白酶(MMPs)、MMP2和MMP9与这些肿瘤有关 人类的进展性事件。因此，他们是潜在的目标。 抗癌药物的设计，因为它们独特的底物特异性和 与肿瘤相关的活动。这个项目的总体目标是设计， 新型人基质金属蛋白酶-2非肽类抑制剂的合成与开发 和-9作为潜在的抗转移剂。协调一致的方法，基于 新的化学模板、酶抑制剂分析和一种新的人类 将采用生物筛选模式。构象受限的新型化合物的合成 基质金属蛋白酶抑制剂将涉及P1-P1的特定取代 磺胺分子的亚基。根据初步研究，我们假设 我们的活性位点定向的分子修饰将提供高效力和 靶向MMPs中对抑制剂的选择性。我们团队的努力将有两个 具体目标：1.开发新型基质金属蛋白酶选择性非肽基抑制剂 构象限制化学与结构辅助建模 策略，以及2.评估铅基质金属蛋白酶抑制剂的功能疗效 我们定义了肿瘤血管生成、侵袭和转移的人体生物检测方法，并启动了药理学研究。第一阶段任务将确定新的 合成第二代强效化合物所需的抑制剂模板 基质金属蛋白酶特异性化合物。基质金属蛋白酶-2和-9的平行结构-功能研究 模型抑制剂将为改善药代动力学提供新的见解 和生物功效。人类肿瘤生物检测将阐明 选择性抑制基质金属蛋白酶对早期(血管生成)和晚期(侵袭)的作用 转移的可能性。还将对基质金属氧化物催化域的三维结构进行研究 进一步协助我们的药物设计策略。这项生物评估将 对随后的体内潜在抗癌试验具有临床意义 探员们。因此，未来临床试验的科学基础和理论基础 对于新的治疗药物的商业化，应该为 肿瘤患者易受基质金属蛋白酶-2和-9的抑制。 建议的商业应用： 成功开发有效的基质金属蛋白酶选择性抑制剂作为抗癌药物将对基础和临床研究产生影响，并将转化为治疗领域。一种生物活性的抗血管生成/抗肿瘤药物将有一个潜在的巨大的全球市场。关键MMPs的合成抑制剂还将使其他相关生物医学领域受益，包括关节炎、纤维化和血管生物学。

DESCRIPTION (provided by applicant): Metastatic spread of cancer via proteolytic degradation of host biomatrix continues to be the greatest barrier to cancer cure. Two key matrix-degrading metalloproteinases (MMPs), MMP-2 and -9, are implicated in these tumor progression events in humans. They are, therefore, targets for potential anticancer drug design because of their unique substrate specificity and tumor-related activities. The overall goal of this project is to design, synthesize and develop novel nonpeptidyl inhibitors selective for human MMP-2 and -9 as potential antimetastatic agents. A concerted approach based on novel chemical templates, enzyme-inhibitor analysis and a new human bioscreening model will be employed. The synthesis of new conformationally-restrained MMP inhibitors will involve specific substitutions at the P1-P1 subsites of sulfonamide molecules. Based on pilot studies, we postulate that our active site-directed molecular modifications will render high potency and selectivity to inhibitors in target MMPs. Our team effort will have two specific goals: 1. Develop novel MMP-selective nonpeptidyl inhibitors using conformational-restriction chemistry and structure-assisted modeling strategies, and 2. Evaluate functional efficacy of lead MMP inhibitors using our defined human bioassays of tumor angiogenesis, invasion and metastasis, and initiate pharmacological studies. Phase I tasks will identify new inhibitor templates necessary for the synthesis of second-generation potent MMP-specific compounds. Parallel structure-function studies of MMP-2 and -9 with model inhibitors will provide new insights to improve pharmacokinetics and bioefficacy. Human tumor bioassays will elucidate the consequences of selective MMP inhibition on early (angiogenesis) and later (invasion) stages of metastasis. 3-D structural studies of MMP catalytic domains will also be exploited to further assist our drug design strategy. This bioevaluation will be clinically relevant for subsequent in vivo testing of potential anticancer agents. Thus, the scientific basis for future clinical trials and rationale for commercialization of new therapeutic drugs should be established for patients with cancers susceptible to MMP-2 and -9 inhibition. PROPOSED COMMERCIAL APLICATION: Successful development of potent MMP-selective inhibitors as anticancer agents will impact both basic & clinical research and be translated into the therapeutic arena. A bioactive antiangiogenic/antimetastic agent would have a potentially large world-wide market. Synthetic inhibitors of key MMPs will also benefit other related biomedical fields including arthritis, fibrosis and vascular biology.