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.

对于新疗法，仍存在巨大的需要，以治疗肿瘤进展并预防肿瘤转移。 基质金属蛋白酶（MMP）是一个在这些事件中具有明显作用的酶。拟议的研究的长期目标是得出对MMP活性位点的结构和功能的理解，并应用此理解以使MMP的新拮抗剂成为抗肿瘤剂。 大量证据表明基质金属蛋白酶（MMP）是因果 参与肿瘤进展和转移。然而，开发矩阵的十年努力 金属蛋白酶抑制剂（MMPI）并在临床领域进行测试现已失去动力。这会产生悖论；我们知道MMP是有效的靶标，但是在临床试验中，药物令人失望。 许多因素导致MPI在诊所失败。这些因素包括 对癌症中MMP的病理生理的不完全了解，无法监测MMP 体内抑制作用，缺乏选择性抑制剂。拟议的研究的目的是克服阻止MMPI在肿瘤学临床试验中实现其诺言的障碍。 拟议的研究的具体目的是：1）确定与肿瘤相关的MMP的最佳和选择性肽底物，然后使用这些鉴定荧光，近红外荧光和磁共振成像剂，并报告体内MMP活性的磁共振成像。底物还将用作MMP活动位点中探测结构 - 活性关系的指南。 2）开发一个可公开访问的计算环境，称为蛋白水解图，以指导基因组量表上有关蛋白水解的推理。 3）使用质谱法鉴定MMP-7，MMP-2和MMP-9的病理生理底物，特别强调了这些MMPS参与肿瘤进展的小鼠模型。 3）MMP-7和MMP-9的设计新颖和选择性的小分子拮抗剂。 虚拟对接和/或NMR筛选将用于识别击中催化裂缝中82个亚铁矿的化学引线。这些化学引线将通过基于迭代结构的修饰来改善，并将在基于细胞的测定中测试，并最终在肿瘤进展的动物模型中进行测试。