title: A sulfoximine-based inhibitor of human asparagine synthetase kills L-asparaginase-resistant leukemia cells.
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)(∗)=8 nM) 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 0.25 mM 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.
authors.affiliation: Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ikeuchi
authors.forename: Yong-Mo
authors.initials: YM
authors.lastname: Ahn
authors.forename: Takuya
authors.initials: T
authors.lastname: Otokawa
authors.forename: Bunta
authors.initials: B
authors.lastname: Watanabe
authors.forename: Lamees
authors.initials: L
authors.lastname: Hegazy
authors.forename: Jun
authors.initials: J
authors.lastname: Hiratake
authors.forename: Nigel G J
authors.initials: NG
authors.lastname: Richards
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001215:Asparaginase / Q000378:metabolism*; D001216:Asparagine / Q000378:metabolism; D001217:Aspartate-Ammonia Ligase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007097:Imines / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology*; D013457:Sulfur Compounds / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007097:Imines; D013457:Sulfur Compounds; D001216:Asparagine; D000581:Amidohydrolases; C425491:N-terminal asparagine amidohydrolase; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase