Metalloproteinases in Tumor Progression and Metastasis

肿瘤进展和转移中的金属蛋白酶

• 批准号: 6922488
• 负责人: Jeffrey W Smith
• 金额: $ 49.37万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6922488
• 关键词: active sites; antineoplastics; bioimaging /biomedical imaging; drug discovery /isolation; enzyme structure; enzyme substrate; genetically modified animals; laboratory mouse; magnetic resonance imaging; mass spectrometry; metalloendopeptidases; metastasis; molecular /cellular imaging; molecular probes; neoplastic growth; neoplastic process; protease inhibitor; protein structure function; structural biology; technology /technique development

A great need still exists for new therapies to treat tumor progression and to prevent tumor metastasis. The matrix metalloproteinases (MMPs) are one family of enzymes that have a clear role in these events. The long-term objective of the proposed study is to derive an understanding of the structure and function of the MMP active site and to apply this understanding to bring forward new antagonists of the MMPs as anti-tumor agents. An overwhelming body of evidence indicates that matrix metalloproteinases (MMPs) are causally involved in tumor progression and metastasis. Yet a decade-long effort of developing matrix metalloproteinase inhibitors (MMPIs) and testing them in the clinical arena has now lost momentum. This creates a paradox; we know the MMPs are valid targets, but the drugs were disappointing in clinical trials. A number of factors contributed to the failure of the MPIs in the clinic. These factors include an incomplete understanding of the pathophysiology of MMPs in cancer, the inability to monitor MMP inhibition in vivo, and the lack of selective inhibitors. The objective of the proposed study is to overcome the hurdles that prevented the MMPI's from realizing their promise in clinical trials in oncology. The Specific Aims of the proposed study are to: 1) Identify optimal and selective peptide substrates for tumor-associated MMPs and then use these to develop fluorescent, near-infrared fluorescent, and magnetic resonance imaging agents that report on the MMP activity in vivo. The substrates will also be used as a guide to probe structure-activity relationships within the MMP active site. 2) Develop a publicly accessible computational environment, called Proteolysis MAP, to guide reasoning about proteolysis on a genome scale. 3) Use mass spectrometry to identify the pathophysiologic substrates for MMP-7, MMP-2 and MMP-9, with particular emphasis on mouse models where these MMPs are known to be involved in tumor progression. 3) Design novel and selective small molecule antagonists of MMP-7 and MMP-9. Virtual docking and/or NMR screening will be used to identify chemical leads that hit the 82 subsite in the catalytic cleft. These chemical leads will be improved by iterative structure-based modifications and will be tested in cell-based assays and ultimately in animal models of tumor progression.

仍然非常需要治疗肿瘤进展和预防肿瘤转移的新疗法。 基质金属蛋白酶 (MMP) 是在这些事件中发挥明显作用的酶家族。本研究的长期目标是了解 MMP 活性位点的结构和功能，并应用这种理解来提出新的 MMP 拮抗剂作为抗肿瘤药物。 大量证据表明基质金属蛋白酶 (MMP) 与 参与肿瘤的进展和转移。然而，矩阵的开发却花费了十年的时间 金属蛋白酶抑制剂（MMPI）及其在临床领域的测试现已失去动力。这就产生了一个悖论；我们知道 MMP 是有效的靶点，但这些药物在临床试验中的表现令人失望。 许多因素导致 MPI 在临床上的失败。这些因素包括 对癌症中 MMP 的病理生理学了解不完全，无法监测 MMP 体内抑制作用，且缺乏选择性抑制剂。拟议研究的目的是克服阻碍 MMPI 在肿瘤学临床试验中实现其承诺的障碍。 该研究的具体目标是：1) 确定肿瘤相关 MMP 的最佳和选择性肽底物，然后使用它们开发荧光、近红外荧光和磁共振成像剂，报告体内 MMP 活性。这些底物还将用作探测 MMP 活性位点内结构-活性关系的指南。 2) 开发一个可公开访问的计算环境，称为“蛋白水解MAP”，以指导基因组规模上蛋白水解的推理。 3) 使用质谱法鉴定 MMP-7、MMP-2 和 MMP-9 的病理生理底物，特别强调已知这些 MMP 参与肿瘤进展的小鼠模型。 3）设计新型选择性MMP-7和MMP-9小分子拮抗剂。 虚拟对接和/或 NMR 筛选将用于识别撞击催化裂隙中 82 亚位点的化学先导物。这些化学先导化合物将通过基于结构的迭代修饰进行改进，并将在基于细胞的测定中进行测试，并最终在肿瘤进展的动物模型中进行测试。