Intervention of Disease by Selective Gelatinase Inhibitors

描述（由申请人提供）：许多疾病的病理表现为组织周围基质的降解。这些疾病中的两种是中风和转移性癌症，这两种疾病是本赠款申请的研究目标。有证据表明，锌依赖性内肽酶的基质金属蛋白酶（MMP）家族的成员，其中26个是已知的，在这些过程中发挥关键作用。特别是，有明确的迹象表明，明胶酶（MMP-2和MMP-9）是主要的贡献者。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剂，但在晚期癌症患者的临床试验中产生严重的副作用。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已被假定为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，并设计了第一个机制为基础的（自杀）抑制剂（抑制剂1），这是高度选择性的明胶酶（MMP-2和MMP-9），证明了在体外研究与纯化的酶。抑制剂1在两种不同癌症和中风的啮齿动物模型中也有活性。尽管抑制剂1的早期前景，但该分子并没有准备好向前发展，因为它是水溶性差的，并且很容易代谢。本文公开的科学旨在设计下一代这种类型的抑制剂，其注意改进的靶向选择性、更好的水溶性、期望的药代动力学性质和先导物优化，这将使项目朝着临床前开发和随后进入临床试验的方向发展。对中风和侵袭性转移性癌症进行干预的临床需求是真实的。本文公开的科学在满足临床挑战方面有希望。 当癌症在体内扩散（转移）时，它就变成了一种致命的疾病。同样，中风是社区的一大杀手。癌症的扩散和中风后的脑损伤有许多共同的特征，这些特征是本补助金申请的主题。申请人已经开发出一类分子，可以防止癌症扩散，并防止中风导致的脑细胞死亡。目前的拨款申请试图提出这类药物的成员进行临床前开发。

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.