Intervention of Disease by Selective Gelatinase Inhibitors

描述(申请人提供)：许多疾病的病理表现为周围组织基质的降解。这些疾病中有两种是中风和转移性癌症，这两种疾病是这次拨款申请的研究对象。有证据表明，基质金属蛋白酶(MMPs)家族的成员在这些过程中发挥着关键作用，其中26个是已知的锌依赖内肽酶。特别是，有明确的迹象表明，明胶酶(基质金属蛋白酶-2和基质金属蛋白酶-9)是主要贡献者。在癌症动物模型中，广谱合成的基质金属蛋白酶抑制剂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MMPs和几种相关金属蛋白酶的广泛抑制特性被认为是造成这些困难和不良副作用的主要原因之一。我们已经回答了这一挑战，并设计了第一个基于机制的(自杀)抑制物(抑制物1)，它对明胶酶(MMP2和MMP9)具有高度的选择性，纯化的酶的体外研究证明了这一点。抑制物1在两种截然不同的癌症和中风的啮齿动物模型中也是活跃的。尽管抑制物1的早期承诺，但该分子并不准备向前推进，因为它很难溶于水，而且很容易代谢。本文所披露的科学旨在设计下一代这种类型的抑制剂，关注于改善靶向的选择性、更好的水溶解性、所需的药代动力学特性和先导优化，这将推动该项目朝着临床前开发和随后进入临床试验的方向发展。介入中风和侵袭性转移性癌症的临床需求是真实的。这里披露的科学在迎接临床挑战方面前景看好。 当癌症在体内扩散(转移)时，它就成为一种致命的疾病。同样，中风是社区中的一大杀手。癌症的扩散和中风后的脑损伤具有许多共同的特征，这些都是这项赠款申请的主题。拨款申请者已经开发出一类分子，可以防止癌症扩散和防止脑细胞因中风而死亡。目前的赠款申请试图将这类药物的成员提前进行临床前开发。

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.