Design & Discovery of Novel Antimetastatic MMP Inhibitor

描述（由申请人提供）： 通过宿主生物基质的蛋白水解降解的癌症转移扩散 仍然是癌症治疗的最大障碍。双键矩阵降阶 金属蛋白酶（MMP-2和MMP-9）与这些肿瘤有关 人类的进展事件。因此，他们是潜在的目标， 抗癌药物设计，因为它们独特的底物特异性， 肿瘤相关活动。该项目的总体目标是设计， 人MMP-2选择性非肽类抑制剂合成与开发 和-9作为潜在的抗转移剂。一种协调一致的办法， 新的化学模板，酶抑制剂分析和一个新的人类 将采用生物筛选模型。新型构象抑制剂的合成 MMP抑制剂将涉及P1-P1位点的特异性取代， 磺酰胺分子的亚位点。根据试点研究，我们假设， 我们的活性定点分子修饰将提供高效力， 对靶MMPs中抑制剂的选择性。我们的团队努力将有两个 具体目标：1.使用药物开发新型MMP选择性非肽基抑制剂 构象限制化学和结构辅助建模 战略，2。使用以下指标评价MMP抑制剂的功能疗效 我们定义的肿瘤血管生成、侵袭和转移的人体生物测定，并启动药理学研究。第一阶段的任务将确定新的 抑制剂模板合成第二代强效 MMP特异性化合物。MMP-2和MMP-9的平行结构-功能研究 与模型抑制剂将提供新的见解，以改善药代动力学 和生物功效。人类肿瘤生物测定将阐明 对早期（血管生成）和晚期（侵袭）阶段的选择性MMP抑制 转移。MMP催化结构域的三维结构研究也将在 进一步协助我们的药物设计策略。本生物评价将 与潜在抗癌药物的后续体内试验具有临床相关性 剂.从而为今后的临床试验提供科学依据和理论依据 新的治疗药物的商业化应建立 对MMP-2和MMP-9抑制敏感的癌症患者。 拟议商业应用： 有效的MMP选择性抑制剂作为抗癌剂的成功开发将影响基础和临床研究，并将转化为治疗竞技场。 具有生物活性的抗血管生成/抗转移剂将具有潜在的巨大的全球市场。 关键MMPs的合成抑制剂也将有益于其他相关的生物医学领域，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.