Development of sulfonamide compounds as potent methionine aminopeptidase type II inhibitors with antiproliferative properties.
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.
Kawai
Megumi
M
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. megumi.kawai@abbott.com
BaMaung
Nwe Y
NY
Fidanze
Steve D
SD
Erickson
Scott A
SA
Tedrow
Jason S
JS
Sanders
William J
WJ
Vasudevan
Anil
A
Park
Chang
C
Hutchins
Charles
C
Comess
Kenneth M
KM
Kalvin
Douglas
D
Wang
Jieyi
J
Zhang
Qian
Q
Lou
Pingping
P
Tucker-Garcia
Lora
L
Bouska
Jennifer
J
Bell
Randy L
RL
Lesniewski
Richard
R
Henkin
Jack
J
Sheppard
George S
GS
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*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006023:Glycoproteins; D013449:Sulfonamides; D008345:Manganese; D000626:Aminopeptidases; C081311:METAP2 protein, human; D063208:Methionyl Aminopeptidases