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）：许多疾病通过周围组织的基质降解表现出其病理。这些疾病中的两种是该赠款应用的调查靶标，是中风和转移性癌症。有证据表明，基质金属蛋白酶（MMP）家族的锌依赖性内肽酶的成员在这些过程中起着关键作用。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。广谱合成的MMP抑制剂被证明是癌症动物模型的有效抗癌药，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作用已被认为是困难和不希望的副作用的主要原因之一。我们已经回答了这一挑战，并设计了对明胶酶（MMP-2和MMP-9）高度选择性的第一个基于机制的（自杀）抑制剂（抑制剂1），这是通过纯化酶进行体外研究所证明的。抑制剂1在两种不同的癌症和中风的啮齿动物模型中也有效。尽管抑制剂1的早期有望，但由于水溶性较差，并且很容易代谢，因此该分子没有准备向前移动。本文所披露的科学旨在设计下一代这种抑制剂，并注意提高靶向选择性，更好的水溶性，理想的药代动力学特性和铅优化，这将使项目朝着临床前开发以及随后进入临床试验的方向发展。中风干预和侵略性转移性癌症的临床需求是真实的。本文披露的科学在应对临床挑战方面有希望。 当癌症在体内扩散（转移）时，它会成为一种致命的疾病。同样，中风是社区中的大杀手。中风后癌症和脑损伤的传播具有许多特征，这些特征是本赠款应用的主题。赠款申请人已经开发了一类分子，这些分子可以防止癌症扩散并防止脑细胞死亡。目前的赠款申请试图提出这类药物的成员进行临床前开发。