2013 Fiscal Year Final Research Report
Drug design based on asparagine synthetase inhibitors
| Project/Area Number |
23510278
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Chemical biology
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| Research Institution | Kyoto University |
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Principal Investigator |
HIRATAKE Jun 京都大学, 化学研究所, 教授 (80199075)
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| Co-Investigator(Kenkyū-buntansha) |
WATANABE Bunta 京都大学, 化学研究所, 助教 (10544637)
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| Project Period (FY) |
2011 – 2013
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| Keywords | ヒトアスパラギン合成酵素 / 遷移状態アナログ阻害剤 / 急性リンパ性白血病 / 化学療法 / アシルアデニル酸中間体 / アデノシンミミック |
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| Research Abstract |
Human asparagine synthetase (hAS) is responsible for leukemia cells to acquire a resistant phenotype for asparaginase, a currently well-adopted chemotherapy to treat acute lymphoblastic leukemia (ALL). The purpose of this study is to design, synthesis and evaluation of novel and potent inhibitors of hAS for developing a new drug lead for asparaginase-resistant leukemia. According to the catalytic mechanism of hAS, we have developed a series of N-adenosylsulfoximines as transition-state analogue inhibitors of hAS. The N-adenosylsulfoximines were found to inhibit hAS strongly in a time-dependent manner with an overall inhibition constant (Ki*) of 7.6 nM. Interestingly, the N-adenosylsulfoximine caused cell death as well as inhibition of cell proliferation of asparaginase-resistant leukemia cells. Thus we have shown that hAS is a highly promising target for anti-leukemia chemotherapy in the current clinical settings and that the N-adenosylsulfoximines serves as a promising drug lead.
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