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Title: A sulfoximine-based inhibitor of human asparagine synthetase kills l-asparaginase-resistant leukemia cells.
Authors: Ikeuchi, Hideyuki
Ahn, Yong-Mo
Otokawa, Takuya
Watanabe, Bunta  kyouindb  KAKEN_id  orcid (unconfirmed)
Hegazy, Lamees
Hiratake, Jun
Richards, Nigel G J
Author's alias: 平竹, 潤
Keywords: Acute lymphoblastic leukemia
Asparagine synthetase
Transition-state analogue inhibitor
Structure–activity relationship
MOLT-4 leukemia cell line
l-Asparagine amidohydrolase
Cell death
Issue Date: Oct-2012
Publisher: Elsevier Ltd.
Journal title: Bioorganic & medicinal chemistry
Volume: 20
Issue: 19
Start page: 5915
End page: 5927
Abstract: An adenylated sulfoximine transition-state analogue 1, which inhibits human asparagine synthetase (hASNS) with nanomolar potency, has been reported to suppress the proliferation of an l-asparagine amidohydrolase (ASNase)-resistant MOLT-4 leukemia cell line (MOLT-4R) when l-asparagine is depleted in the medium. We now report the synthesis and biological activity of two new sulfoximine analogues of 1 that have been studied as part of systematic efforts to identify compounds with improved cell permeability and/or metabolic stability. One of these new analogues, an amino sulfoximine 5 having no net charge at cellular pH, is a better hASNS inhibitor (K(I)(∗)=8nM) than 1 and suppresses proliferation of MOLT-4R cells at 10-fold lower concentration (IC(50)=0.1mM). More importantly, and in contrast to the lead compound 1, the presence of sulfoximine 5 at concentrations above 0.25mM causes the death of MOLT-4R cells even when ASNase is absent in the culture medium. The amino sulfoximine 5 exhibits different dose-response behavior when incubated with an ASNase-sensitive MOLT-4 cell line (MOLT-4S), supporting the hypothesis that sulfoximine 5 exerts its effect by inhibiting hASNS in the cell. Our work provides further evidence for the idea that hASNS represents a chemotherapeutic target for the treatment of leukemia, and perhaps other cancers, including those of the prostate.
Rights: © 2012 Elsevier Ltd.
This is not the published version. Please cite only the published version.
DOI(Published Version): 10.1016/j.bmc.2012.07.047
PubMed ID: 22951255
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