title: Development of sulfonamide compounds as potent methionine aminopeptidase type II inhibitors with antiproliferative properties.
abstract: We have screened molecules for inhibition of MetAP2 as a novel approach toward antiangiogenesis and anticancer therapy using affinity selection/mass spectrometry (ASMS) employing MetAP2 loaded with Mn(2+) as the active site metal. After a series of anthranilic acid sulfonamides with micromolar affinities was identified, chemistry efforts were initiated. The micromolar hits were quickly improved to potent nanomolar inhibitors by chemical modifications guided by insights from X-ray crystallography.
authors.affiliation: Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. megumi.kawai@abbott.com
authors.forename: Megumi
authors.initials: M
authors.lastname: Kawai
authors.forename: Nwe Y
authors.initials: NY
authors.lastname: BaMaung
authors.forename: Steve D
authors.initials: SD
authors.lastname: Fidanze
authors.forename: Scott A
authors.initials: SA
authors.lastname: Erickson
authors.forename: Jason S
authors.initials: JS
authors.lastname: Tedrow
authors.forename: William J
authors.initials: WJ
authors.lastname: Sanders
authors.forename: Anil
authors.initials: A
authors.lastname: Vasudevan
authors.forename: Chang
authors.initials: C
authors.lastname: Park
authors.forename: Charles
authors.initials: C
authors.lastname: Hutchins
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Comess
authors.forename: Douglas
authors.initials: D
authors.lastname: Kalvin
authors.forename: Jieyi
authors.initials: J
authors.lastname: Wang
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Pingping
authors.initials: P
authors.lastname: Lou
authors.forename: Lora
authors.initials: L
authors.lastname: Tucker-Garcia
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bouska
authors.forename: Randy L
authors.initials: RL
authors.lastname: Bell
authors.forename: Richard
authors.initials: R
authors.lastname: Lesniewski
authors.forename: Jack
authors.initials: J
authors.lastname: Henkin
authors.forename: George S
authors.initials: GS
authors.lastname: Sheppard
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008345:Manganese / Q000737:chemistry; D013058:Mass Spectrometry / Q000379:methods; D063208:Methionyl Aminopeptidases; D008958:Models, Molecular; D015394:Molecular Structure; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006023:Glycoproteins; D013449:Sulfonamides; D008345:Manganese; D000626:Aminopeptidases; C081311:METAP2 protein, human; D063208:Methionyl Aminopeptidases