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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078743-16
Application #
8250456
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Misra, Raj N
Project Start
2008-06-01
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
16
Fiscal Year
2012
Total Cost
$365,100
Indirect Cost
$142,478
Name
Johns Hopkins University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Zhang, Feiran; Bhat, Shridhar; Gabelli, Sandra B et al. (2013) Pyridinylquinazolines selectively inhibit human methionine aminopeptidase-1 in cells. J Med Chem 56:3996-4016
Bhat, Shridhar; Shim, Joong Sup; Liu, Jun O (2013) Tricyclic thiazoles are a new class of angiogenesis inhibitors. Bioorg Med Chem Lett 23:2733-7
Zhang, Pengtao; Yang, Xinye; Zhang, Feiran et al. (2013) Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1. Bioorg Med Chem 21:2600-17
Bhat, Shridhar; Shim, Joong Sup; Zhang, Feiran et al. (2012) Substituted oxines inhibit endothelial cell proliferation and angiogenesis. Org Biomol Chem 10:2979-92
Chamni, Supakarn; He, Qing-Li; Dang, Yongjun et al. (2011) Diazo reagents with small steric footprints for simultaneous arming/SAR studies of alcohol-containing natural products via O-H insertion. ACS Chem Biol 6:1175-81
Xiao, Qing; Zhang, Feiran; Nacev, Benjamin A et al. (2010) Protein N-terminal processing: substrate specificity of Escherichia coli and human methionine aminopeptidases. Biochemistry 49:5588-99
Hu, Xiaoyi V; Chen, Xiaochun; Han, Kee Chung et al. (2007) Kinetic and mutational studies of the number of interacting divalent cations required by bacterial and human methionine aminopeptidases. Biochemistry 46:12833-43
Peddibhotla, Satyamaheshwar; Dang, Yongjun; Liu, Jun O et al. (2007) Simultaneous arming and structure/activity studies of natural products employing O-H insertions: an expedient and versatile strategy for natural products-based chemical genetics. J Am Chem Soc 129:12222-31
Addlagatta, Anthony; Hu, Xiaoyi; Liu, Jun O et al. (2005) Structural basis for the functional differences between type I and type II human methionine aminopeptidases. Biochemistry 44:14741-9
Boxem, Mike; Tsai, Chiawei W; Zhang, Yi et al. (2004) The C. elegans methionine aminopeptidase 2 analog map-2 is required for germ cell proliferation. FEBS Lett 576:245-50