Structure, Function and Inhibition of Human Methionine Aminopeptidases

点击翻译按钮获取中文摘要

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.