title: Tumor suppression by a rationally designed reversible inhibitor of methionine aminopeptidase-2.
abstract: 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.
authors: Cancer Research, Global Pharmaceutical R & D, Abbott Laboratories, Abbott Park, IL 60064, USA. Jieyi.Wang@abbott.com
authors: Jieyi
authors: J
authors: Wang
authors: George S
authors: GS
authors: Sheppard
authors: Pingping
authors: P
authors: Lou
authors: Megumi
authors: M
authors: Kawai
authors: Nwe
authors: N
authors: BaMaung
authors: Scott A
authors: SA
authors: Erickson
authors: Lora
authors: L
authors: Tucker-Garcia
authors: Chang
authors: C
authors: Park
authors: Jennifer
authors: J
authors: Bouska
authors: Yi-Chun
authors: YC
authors: Wang
authors: David
authors: D
authors: Frost
authors: Paul
authors: P
authors: Tapang
authors: Daniel H
authors: DH
authors: Albert
authors: Sherry J
authors: SJ
authors: Morgan
authors: Michael
authors: M
authors: Morowitz
authors: Suzanne
authors: S
authors: Shusterman
authors: John M
authors: JM
authors: Maris
authors: Rick
authors: R
authors: Lesniewski
authors: Jack
authors: J
authors: Henkin
mesh_terms: 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
chemical_list: 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