title: Methionine AminoPeptidase Type-2 Inhibitors Targeting Angiogenesis.
abstract: Angiogenesis has been identified as a crucial process in the development and spread of cancers. There are many regulators of angiogenesis which are not yet fully understood. Methionine aminiopeptidase is a metalloenzyme with two structurally distinct forms in humans, Type-1 (MetAP-1) and Type-2 (MetAP-2). It has been shown that small molecule inhibitors of MetAP-2 suppress endothelial cell proliferation. The initial discovery by Donald Ingber of MetAP-2 inhibition as a potential target in angiogenesis began with a fortuitous observation similar to the discovery of penicillin activity by Sir Alexander Fleming. From a drug design perspective, MetAP-2 is an attractive target. Fumagillin and ovalicin, known natural products, bind with IC50 values in low nanomolar concentrations. Crystal structures of the bound complexes provide 3-dimensional coordinates for advanced computational studies. More recent discoveries have shown other biological activities for MetAP-2 inhibition, which has generated new interests in the design of novel inhibitors. Semisynthetic fumagillin derivatives such as AGM-1470 (TNP-470) have been shown to have better drug properties, but have not been very successful in clinical trials. The rationale and development of novel multicyclic analogs of fumagillin are reviewed.
authors.forename: Tedman
authors.initials: T
authors.lastname: Ehlers
authors.forename: Scott
authors.initials: S
authors.lastname: Furness
authors.forename: Thomas Philip
authors.initials: TP
authors.lastname: Robinson
authors.forename: Haizhen A
authors.initials: HA
authors.lastname: Zhong
authors.forename: David
authors.initials: D
authors.lastname: Goldsmith
authors.forename: Jack
authors.initials: J
authors.lastname: Aribser
authors.affiliation: Center for Drug Design, Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, 3001 Mercer University Drive, Atlanta, Georgia 30341, U.S.A. bowen_jp@mercer.edu.
authors.forename: J Phillip
authors.initials: JP
authors.lastname: Bowen
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003510:Cyclohexanes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D063208:Methionyl Aminopeptidases; D008958:Models, Molecular; D008968:Molecular Conformation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D012717:Sesquiterpenes; D000626:Aminopeptidases; C081311:METAP2 protein, human; D063208:Methionyl Aminopeptidases; D000077609:O-(Chloroacetylcarbamoyl)fumagillol