Intervention of Disease by Selective Gelatinase Inhibitors

选择性明胶酶抑制剂对疾病的干预

• 批准号: 7665470
• 负责人: Mayland F Chang
• 金额: $ 37.82万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-07 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7665470
• 关键词: Advanced Malignant Neoplasm; Adverse effects; Animal Cancer Model; Antimetastatic Agent; Antineoplastic Agents; Applications Grants; Attention; Brain Injuries; Cell Death; Characteristics; Clinical; Clinical Trials; Communities; Development; Disease; Disseminated Malignant Neoplasm; Drug Kinetics; Endopeptidases; Enzymes; Evaluation; Family; Gelatinase A; Gelatinase B; Gelatinases; Grant; In Vitro; Intervention; Investigation; Lead; Libraries; Malignant Neoplasms; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Metalloproteases; Neoplasm Metastasis; Pathology; Patients; Pharmaceutical Preparations; Plant Roots; Play; Principal Investigator; Process; Property; Rodent Model; Role; Science; Solubility; Stroke; Structure; Tissues; Variant; Water; Zinc; aqueous; base; brain cell; combinatorial; design; improved; in vivo; inhibitor/antagonist; meetings; member; next generation; novel; pre-clinical; prevent; programs; structural biology; suicide inhibitor

DESCRIPTION (provided by applicant): A number of diseases manifest their pathology by degradation of the matrix surrounding tissues. Two of these diseases, targets of investigation by this grant application, are stroke and metastatic cancer. Evidence has shown that members of the matrix metalloproteinase (MMP) family of zinc-dependent endopeptidases, of which 26 are known, play key roles in these processes. In particular, there is clear indication that gelatinases (MMP-2 and MMP-9) are major contributors. Broad-spectrum synthetic MMP inhibitors were shown to be effective anti-cancer agents in animal models of cancer, but produced serious side effects in clinical trials in patients with advanced cancer. Broad inhibitory properties of these inhibitors against all MMPs and several related metalloproteinases have been postulated as one of the major reasons for the difficulties and the undesired side effects. We have answered this challenge and have devised the first mechanism-based (suicide) inhibitor (inhibitor 1) that is highly selective for gelatinases (MMP-2 and MMP-9), as evidenced by in vitro investigations with purified enzymes. Inhibitor 1 is also active in rodent models for two distinct cancers and stroke. Despite the early promise of inhibitor 1, the molecule is not poised to move forward, as it is poorly water soluble and it is readily metabolized. The science disclosed herein is intended to devise the next generation of this type of inhibitor with attention to improved selectivity in targeting, better aqueous solubility, desirable pharmacokinetic properties and lead optimization, which would move the project in the direction of preclinical development and subsequent entry into clinical trials. The clinical needs for intervention of stroke and of aggressive metastatic cancers are genuine. The science disclosed herein holds promise in meeting the clinical challenges. When cancer spreads in the body (metastasis), it becomes a fatal disease. Similarly, stroke is a big killer in the community. Spread of cancer and brain damage after stroke share a number of characteristics that are the subjects of this grant application. The grant applicants have developed a class of molecules that prevent cancer from spreading and prevent brain cell death due to stroke. The present grant application attempts to bring forward members of this type of drug forward for preclinical development.

描述（由申请人提供）：许多疾病通过组织周围基质的降解来表现其病理学。其中两种疾病是本次拨款申请的研究目标，即中风和转移性癌症。有证据表明，锌依赖性内肽酶基质金属蛋白酶 (MMP) 家族的成员（其中已知 26 种）在这些过程中发挥着关键作用。特别是，有明确的迹象表明明胶酶（MMP-2 和 MMP-9）是主要贡献者。广谱合成 MMP 抑制剂在癌症动物模型中被证明是有效的抗癌药物，但在晚期癌症患者的临床试验中产生了严重的副作用。这些抑制剂对所有 MMP 和几种相关金属蛋白酶的广泛抑制特性被认为是造成困难和不良副作用的主要原因之一。我们已经应对了这一挑战，并设计了第一个基于机制的（自杀）抑制剂（抑制剂 1），它对明胶酶（MMP-2 和 MMP-9）具有高度选择性，纯化酶的体外研究证明了这一点。抑制剂 1 在两种不同癌症和中风的啮齿动物模型中也具有活性。尽管抑制剂 1 的早期前景良好，但该分子尚未准备好向前发展，因为它的水溶性很差并且很容易代谢。本文公开的科学旨在设计下一代此类抑制剂，关注改进的靶向选择性、更好的水溶性、理想的药代动力学特性和先导化合物优化，这将使该项目朝着临床前开发和随后进入临床试验的方向发展。干预中风和侵袭性转移性癌症的临床需求是真实的。本文公开的科学有望应对临床挑战。 当癌症在体内扩散（转移）时，它就会成为一种致命的疾病。同样，中风也是社区的一大杀手。癌症扩散和中风后脑损伤有许多共同特征，这些特征都是本次拨款申请的主题。资助申请人开发了一类分子，可以防止癌症扩散并防止中风引起的脑细胞死亡。目前的拨款申请试图推动此类药物的成员进行临床前开发。