Tumor suppression by a rationally designed reversible inhibitor of methionine aminopeptidase-2.
Methionine aminopeptidase (MetAP)-2 has been suggested as a novel target for cancer therapy because the anticancer agent TNP-470 irreversibly inactivates the catalytic activity of this enzyme. However, the importance of MetAP2 in cell growth and tumor progression was uncertain because previous data were based on the chemically reactive TNP-470. Here we show that a rationally designed reversible MetAP2 inhibitor, A-357300, suppresses tumor growth preclinically without the toxicities observed with TNP-470. We have synthesized this bestatin-type MetAP2 inhibitor with the aid of crystal structures of the enzyme-inhibitor complexes and parallel synthesis. A-357300 induces cytostasis by cell cycle arrest at the G(1) phase selectively in endothelial cells and in a subset of tumor cells, but not in most primary cells of nonendothelial type. A-357300 inhibits angiogenesis both in vitro and in vivo and shows potent antitumor efficacy in carcinoma, sarcoma, and neuroblastoma murine models. These data affirm that MetAP2 plays a pivotal role in cell growth and establish that reversible MetAP2 inhibitors are promising novel cancer therapeutic agents.
Wang
Jieyi
J
Cancer Research, Global Pharmaceutical R & D, Abbott Laboratories, Abbott Park, IL 60064, USA. Jieyi.Wang@abbott.com
Sheppard
George S
GS
Lou
Pingping
P
Kawai
Megumi
M
BaMaung
Nwe
N
Erickson
Scott A
SA
Tucker-Garcia
Lora
L
Park
Chang
C
Bouska
Jennifer
J
Wang
Yi-Chun
YC
Frost
David
D
Tapang
Paul
P
Albert
Daniel H
DH
Morgan
Sherry J
SJ
Morowitz
Michael
M
Shusterman
Suzanne
S
Maris
John M
JM
Lesniewski
Rick
R
Henkin
Jack
J
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002722:Chlorobenzenes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D003315:Cornea / Q000098:blood supply; D003510:Cyclohexanes; D015195:Drug Design; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009447:Neuroblastoma / Q000188:drug therapy / Q000201:enzymology; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
C481161:A357300; D000970:Antineoplastic Agents; D002722:Chlorobenzenes; D003510:Cyclohexanes; D011480:Protease Inhibitors; D012717:Sesquiterpenes; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases; D000077609:O-(Chloroacetylcarbamoyl)fumagillol