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周围组织基质的降解。其中两种疾病是本次拨款申请的研究对象，分别是中风和转移性癌症。有证据表明，基质金属蛋白酶（MMP）锌依赖性内肽酶家族的成员，其中26个已知，在这些过程中起关键作用。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）抑制剂（抑制剂1），它对明胶酶（MMP-2和MMP-9）具有高度选择性，正如纯化酶的体外研究所证明的那样。抑制剂1在两种不同的癌症和中风的啮齿动物模型中也很活跃。尽管抑制剂1的早期前景看好，但由于其水溶性差且易于代谢，该分子尚未准备好向前发展。本文披露的科学旨在设计下一代这种类型的抑制剂，其关注于提高靶向选择性，更好的水溶性，理想的药代动力学性质和先导物优化，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。临床需要干预中风和侵袭性转移性癌症是真实的。在此披露的科学在应对临床挑战方面有希望。

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.