Angiogenesis Inhibition: Targeting the MAP-2 enzyme

描述(申请人提供)：血管生成是肿瘤持续生长的必要过程，并为肿瘤转移提供了一种方便的方法。肿瘤利用宿主的血管系统将新血管从宿主引导到肿瘤。这一过程需要内皮细胞分裂和内皮细胞从现有血管迁移到肿瘤肿块。在过去的几年里，对血管生成至关重要的过程已经被识别出来。其中之一是蛋氨酸氨基肽酶2(MAP-2)，它是内皮细胞分裂的关键酶。其他人描述了能够在实验系统中抑制这种酶和防止肿瘤血管生成的小分子。这些分子都是微生物衍生的。我们研究的目标是评估我们的新型微生物来源--地球深层的微生物--产生抑制MAP-2的小分子，然后将这些分子发展成临床实体的能力。为了实现这一目标，我们开发了一种进步的、交互式的生物测定-化学分离方案，使我们能够有效地识别和优先考虑继续进行临床前和临床开发的分子。第一阶段拨款的目标是提供原则证据，证明我们独特的微生物产生这种分子，并且我们可以从微生物发酵液中分离出足够数量的这种分子，以便在第二阶段的研究中继续进行药物发现活动。 拟议的商业应用：癌症是美国人的第二大杀手。转移是癌症死亡的主要原因。一种有效的抗血管生成药物的开发将对我们治疗和控制癌症的能力产生重大影响。市场将是巨大的。

DESCRIPTION (provided by applicant): Angiogenesis is a necessary process for continued tumor growth and provides a convenient method for tumor metastasis. Tumors utilize the host's vascular system to direct new blood vessel formation from the host to the tumor. The process requires endothelial cell division and endothelial cell migration from the existing blood vessel to the tumor mass. Over the past several years, processes critical to angiogenesis have been identified. One of these is the enzyme methionine aminopeptidase 2 (MAP-2), an enzyme pivotal in endothelial cell division. Others have described small molecules capable of inhibiting this enzyme and preventing tumor angiogenesis in experimental systems. These molecules are all microbially derived. The goal of our research is to assess the ability of our novel sources of microbes- the deep subsurface of the Earth- for their ability to produce small molecule that inhibit MAP-2 and then develop these molecules into clinical entities. To accomplish this goal we have developed a progressive, interactive bioassay-chemical isolation protocol that will enable us to effectively identify and prioritize molecules for continued pre-clinical and clinical development. The goal of the Phase 1 grant is to provide proof of principle that our unique microbes produce such molecules and that we can isolate such molecules from microbial broths in sufficient quantities to perform continued drug discovery activities in Phase 2 studies. PROPOSED COMMERCIAL APPLICATION: Cancer is the number 2 killer of Americans. Metastasis is the primary cause of death in cancer. The development of an effective anti-angiogenesis drug would have a dramatic effect on our ability to treat and control cancer. The market would be immense.