title: Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 1.
abstract: Methionine aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhibitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening methods and structural biology to quickly identify and elaborate an indazole fragment into a series of reversible MetAP2 inhibitors with <10nM potency, excellent selectivity, and favorable in vitro safety profiles.
authors.affiliation: Medicinal Chemistry, Takeda California, United States.
authors.forename: Zacharia
authors.initials: Z
authors.lastname: Cheruvallath
authors.affiliation: Medicinal Chemistry, Takeda California, United States.
authors.forename: Mingnam
authors.initials: M
authors.lastname: Tang
authors.affiliation: Medicinal Chemistry, Takeda California, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: McBride
authors.affiliation: Medicinal Chemistry, Takeda California, United States.
authors.forename: Mallareddy
authors.initials: M
authors.lastname: Komandla
authors.affiliation: Medicinal Chemistry, Takeda California, United States.
authors.forename: Joanne
authors.initials: J
authors.lastname: Miura
authors.affiliation: Medicinal Chemistry, Takeda California, United States.
authors.forename: Thu
authors.initials: T
authors.lastname: Ton-Nu
authors.affiliation: Medicinal Chemistry, Takeda California, United States.
authors.forename: Phil
authors.initials: P
authors.lastname: Erikson
authors.affiliation: Medicinal Chemistry, Takeda California, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Biological Sciences, Takeda California, United States.
authors.forename: Pamela
authors.initials: P
authors.lastname: Farrell
authors.affiliation: Computational Sciences, Takeda California, United States.
authors.forename: J David
authors.initials: JD
authors.lastname: Lawson
authors.affiliation: Biological Sciences, Takeda California, United States.
authors.forename: Darin
authors.initials: D
authors.lastname: Vanderpool
authors.affiliation: Biological Sciences, Takeda California, United States.
authors.forename: Yiqin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Structural Biology, Takeda California, United States.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Dougan
authors.affiliation: Biological Sciences, Takeda California, United States.
authors.forename: Artur
authors.initials: A
authors.lastname: Plonowski
authors.affiliation: Biological Sciences, Takeda California, United States.
authors.forename: Corine
authors.initials: C
authors.lastname: Holub
authors.affiliation: Biological Sciences, Takeda California, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Larson
mesh_terms: D000284:Administration, Oral; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D063208:Methionyl Aminopeptidases; D051379:Mice; D008820:Mice, Obese; D008958:Models, Molecular; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D006023:Glycoproteins; D007191:Indazoles; D000626:Aminopeptidases; C081311:METAP2 protein, human; D063208:Methionyl Aminopeptidases
keywords: FBDD; Fragment-based drug discovery; Indazole; MetAP2; Metalloprotease; Methionine aminopeptidase 2