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，在细胞增殖和生存中发挥重要作用。本应用的主要目的是探索以人甲硫氨酸氨基肽酶(HMetAPs)为靶点及其抑制物作为抗血管生成和抗癌药物开发的先导。HMetAP2被确定为烟青素血管生成抑制剂家族的靶点，随后证实烟美西林及其类似物需要激活P53通路才能抑制内皮细胞。然而，抑制hMetAP2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物。HMetAP1特异性小分子抑制剂和RNA干扰的应用表明，hMetAP1是肿瘤细胞及时进入细胞周期G2/M期所必需的，抑制hMetAP1会导致白血病和淋巴瘤细胞发生凋亡，提示hMetAP1是抗癌药物开发的一个有前景的新靶点。在这一应用中，我们将试图通过鉴定和鉴定参与细胞周期抑制的潜在中介蛋白来阐明这两种类型的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有前景的hMetAP2抑制剂在体外抑制内皮细胞和体内血管生成的潜力。我们将利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的先导化合物。公共卫生相关性蛋氨酸氨基肽酶是进化上高度保守的酶，在细胞增殖和生存中发挥重要作用。本应用的主要目的是探索以人甲硫氨酸氨基肽酶1和2为靶点及其抑制物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.