Structure, Function and Inhibition of Human Methionine Aminopeptidases

描述（由申请人提供）：蛋氨酸氨基肽酶是进化上高度保守的酶，在细胞增殖和存活中起重要作用。本应用程序的主要目的是探索1型和2型人蛋氨酸氨基肽酶（hMetAPs）作为靶点及其抑制剂作为抗血管生成和抗癌药物开发的先导。hMetAP2被确定为富马西林血管生成抑制剂家族的靶点，随后证明激活p53通路是富马西林及其类似物抑制内皮细胞的必要条件。然而，hMetAP2的抑制如何导致p53的激活仍然是一个谜。通过高通量筛选，我们已经确定了hMetAP1和hMetAP2的异构体特异性抑制剂。hMetAP1特异性小分子抑制剂与RNA干扰的应用表明，hMetAP1是肿瘤细胞通过细胞周期G2/M期及时进展所必需的，抑制hMetAP1可导致白血病和淋巴瘤细胞发生凋亡，这表明hMetAP1是抗癌药物开发的一个有希望的新靶点。在本应用中，我们将通过鉴定和表征参与细胞周期抑制的潜在中介蛋白，试图阐明两种hMetAPs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hMetAP2抑制剂在体外抑制内皮细胞和体内血管生成方面的潜力。我们将结合结构生物学和化学技术来提高新发现的抑制剂的效力和异构体特异性，这些抑制剂最终可以作为抗血管生成和抗癌药物开发的先导化合物。蛋氨酸氨基肽酶是进化上高度保守的酶，在细胞增殖和存活中起重要作用。本应用程序的主要目的是探索1型和2型人蛋氨酸氨基肽酶作为靶点及其抑制剂作为抗血管生成和抗癌药物开发的先导。

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.