| Budget Amount *help |
¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2011: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
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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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