title: Discovery and optimization of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2: a structural basis for the reduction of albumin binding.
abstract: Methionine aminopeptidase-2 (MetAP2) is a novel target for cancer therapy. As part of an effort to discover orally active reversible inhibitors of MetAP2, a series of anthranilic acid sulfonamides with micromolar affinities for human MetAP2 were identified using affinity selection by mass spectrometry (ASMS) screening. These micromolar hits were rapidly improved to nanomolar leads on the basis of insights from protein crystallography; however, the compounds displayed extensive binding to human serum albumin and had limited activity in cellular assays. Modifications based on structural information on the binding of lead compounds to both MetAP2 and domain III of albumin allowed the identification of compounds with significant improvements in both parameters, which showed good cellular activity in both proliferation and methionine processing assays.
authors.affiliation: Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Department R47A, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. george.s.sheppard@abbott.com
authors.forename: George S
authors.initials: GS
authors.lastname: Sheppard
authors.forename: Jieyi
authors.initials: J
authors.lastname: Wang
authors.forename: Megumi
authors.initials: M
authors.lastname: Kawai
authors.forename: Steve D
authors.initials: SD
authors.lastname: Fidanze
authors.forename: Nwe Y
authors.initials: NY
authors.lastname: BaMaung
authors.forename: Scott A
authors.initials: SA
authors.lastname: Erickson
authors.forename: David M
authors.initials: DM
authors.lastname: Barnes
authors.forename: Jason S
authors.initials: JS
authors.lastname: Tedrow
authors.forename: Lawrence
authors.initials: L
authors.lastname: Kolaczkowski
authors.forename: Anil
authors.initials: A
authors.lastname: Vasudevan
authors.forename: David C
authors.initials: DC
authors.lastname: Park
authors.forename: Gary T
authors.initials: GT
authors.lastname: Wang
authors.forename: William J
authors.initials: WJ
authors.lastname: Sanders
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mantei
authors.forename: Fabio
authors.initials: F
authors.lastname: Palazzo
authors.forename: Lora
authors.initials: L
authors.lastname: Tucker-Garcia
authors.forename: Pingping
authors.initials: P
authors.lastname: Lou
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Chang H
authors.initials: CH
authors.lastname: Park
authors.forename: Ki H
authors.initials: KH
authors.lastname: Kim
authors.forename: Andrew
authors.initials: A
authors.lastname: Petros
authors.forename: Edward
authors.initials: E
authors.lastname: Olejniczak
authors.forename: David
authors.initials: D
authors.lastname: Nettesheim
authors.forename: Phillip
authors.initials: P
authors.lastname: Hajduk
authors.forename: Jack
authors.initials: J
authors.lastname: Henkin
authors.forename: Richard
authors.initials: R
authors.lastname: Lesniewski
authors.forename: Steven K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: Randy L
authors.initials: RL
authors.lastname: Bell
mesh_terms: D000626:Aminopeptidases / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D008666:Metalloendopeptidases / Q000737:chemistry*; D008715:Methionine / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D012709:Serum Albumin / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D012709:Serum Albumin; D013449:Sulfonamides; D062367:ortho-Aminobenzoates; D008715:Methionine; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases