Discovery and optimization of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2: a structural basis for the reduction of albumin binding.
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.
Sheppard
George S
GS
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
Wang
Jieyi
J
Kawai
Megumi
M
Fidanze
Steve D
SD
BaMaung
Nwe Y
NY
Erickson
Scott A
SA
Barnes
David M
DM
Tedrow
Jason S
JS
Kolaczkowski
Lawrence
L
Vasudevan
Anil
A
Park
David C
DC
Wang
Gary T
GT
Sanders
William J
WJ
Mantei
Robert A
RA
Palazzo
Fabio
F
Tucker-Garcia
Lora
L
Lou
Pingping
P
Zhang
Qian
Q
Park
Chang H
CH
Kim
Ki H
KH
Petros
Andrew
A
Olejniczak
Edward
E
Nettesheim
David
D
Hajduk
Phillip
P
Henkin
Jack
J
Lesniewski
Richard
R
Davidsen
Steven K
SK
Bell
Randy L
RL
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
D000970:Antineoplastic Agents; D012709:Serum Albumin; D013449:Sulfonamides; D062367:ortho-Aminobenzoates; D008715:Methionine; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases