Structure, Function and Inhibition of Human Methionine Aminopeptidases

人蛋氨酸氨基肽酶的结构、功能和抑制

• 批准号: 7835697
• 负责人: Jun O. Liu
• 金额: $ 37.64万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7835697
• 关键词: Affect; Angiogenesis Inhibition; Angiogenesis Inhibitors; Animal Model; Antibiotics; Antineoplastic Agents; Apoptosis; Biology; Cell Culture Techniques; Cell Cycle Inhibition; Cell Proliferation; Cells; Chemistry; Complex; Development; Endothelial Cell Inhibitor; Endothelial Cells; Enzymes; Evaluation; Family; Human; In Vitro; Investigation; Lead; Mediating; Mediator of activation protein; Methods; Microscopic; Mitosis; Molecular; Orthologous Gene; Pathway interactions; Phase; Play; Protein Isoforms; Proteins; Proteomics; RNA Interference; Ras Signaling Pathway; Role; Small Interfering RNA; Specificity; Structure; Structure-Activity Relationship; TNP470; TP53 gene; Techniques; Testing; Ubiquitin-Conjugating Enzymes; Ubiquitination; analog; angiogenesis; base; cyclin B1; design; drug development; fumagillin; high throughput screening; improved; in vivo; inhibitor/antagonist; leukemia/lymphoma; methionyl aminopeptidase; neoplastic cell; nitroxoline; novel; public health relevance; research study; small molecule; structural biology; tumor growth; yeast protein

DESCRIPTION (provided by applicant): Methionine aminopeptidases are evolutionarily highly conserved enzymes that play essential roles in cell proliferation and survival. The main objective of this application is to explore the type 1 and type 2 human methionine aminopeptidases (hMetAPs) as targets and their inhibitors as leads for the development of anti-angiogenic and anti-cancer agents. hMetAP2 was identified as the target of the fumagillin family of angiogenesis inhibitors and it was subsequently demonstrated that activation of the p53 pathway is required for the inhibition of endothelial cells by fumagillin and analogs. However, how inhibition of hMetAP2 leads to the activation of p53 has remained a mystery. Using high-throughput screening, we have identified isoform-specific inhibitors for both hMetAP1 and hMetAP2. Application of hMetAP1-specific small molecule inhibitors along with RNA interference has revealed that hMetAP1 is required for the timely progression of tumor cells through the G2/M phase of the cell cycle and inhibition of hMetAP1 causes leukemia and lymphoma cells to undergo apoptosis, suggesting that hMetAP1 is a promising new target for anticancer drug development. In this application, we will attempt to elucidate the molecular mechanisms of cell cycle inhibition by inhibitors of both types of hMetAPs by identifying and characterizing potential mediator proteins that participate in the cell cycle inhibition. We will assess the potential of a newly identified promising hMetAP2 inhibitor for inhibition of endothelial cells in vitro and angiogenesis in vivo. We will employ a combination of structural biology and chemistry techniques to improve the potency and isoform specificity of newly identified inhibitors, which can eventually serve as lead compounds for the development of anti-angiogenic and anti-cancer drugs. PUBLIC HEALTH RELEVANCE Methionine aminopeptidases are evolutionarily highly conserved enzymes that play essential roles in cell proliferation and survival. The main objective of this application is to explore the type 1 and type 2 human methionine aminopeptidases as targets and their inhibitors as leads for the development of anti-angiogenic and anti-cancer agents.

描述（由申请人提供）：甲氨酰氨基肽酶是进化上高度保守的酶，在细胞增殖和存活中发挥重要作用。本申请的主要目的是探索1型和2型人甲硫氨酸氨基肽酶（hMetAP）作为靶点及其抑制剂作为开发抗血管生成和抗癌剂的先导物。hMetAP 2被鉴定为烟曲霉素家族的血管生成抑制剂的靶标，并且随后证明，烟曲霉素和类似物抑制内皮细胞需要激活p53途径。然而，hMetAP 2的抑制如何导致p53的激活仍然是一个谜。使用高通量筛选，我们已经确定了hMetAP 1和hMetAP 2的亚型特异性抑制剂。沿着RNA干扰的hMetAP 1特异性小分子抑制剂的应用揭示了hMetAP 1是肿瘤细胞通过细胞周期的G2/M期及时进展所必需的，并且hMetAP 1的抑制导致白血病和淋巴瘤细胞经历凋亡，这表明hMetAP 1是抗癌药物开发的有希望的新靶点。在本申请中，我们将试图通过鉴定和表征参与细胞周期抑制的潜在介体蛋白来阐明两种类型的hMetAP抑制剂抑制细胞周期的分子机制。我们将评估一种新发现的有前途的hMetAP 2抑制剂在体外抑制内皮细胞和体内血管生成的潜力。我们将采用结构生物学和化学技术相结合的方法来提高新发现的抑制剂的效力和亚型特异性，这些抑制剂最终可以作为开发抗血管生成和抗癌药物的先导化合物。 甲氨酰氨基肽酶是进化上高度保守的酶，在细胞增殖和存活中发挥重要作用。本申请的主要目的是探索1型和2型人甲硫氨酸氨基肽酶作为靶点及其抑制剂作为开发抗血管生成和抗癌药物的先导。