期刊
ACS CHEMICAL BIOLOGY
卷 8, 期 4, 页码 796-803出版社
AMER CHEMICAL SOC
DOI: 10.1021/cb3005353
关键词
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资金
- National Institutes of Health [R01 DK071976, R21 CA139359]
- UK SPORE grant [P20 CA 150343, R01 DK048498]
- National Center for Research Resources [5P20RR020171-09]
- National Institute of General Medical Sciences from the National Institutes of Health [8 P20 GM103486-09]
Methionine S-adenosyltransferase 2A (MAT2A) is the catalytic subunit for synthesis of S-adenosylmethionine (SAM), the principal methyl donor in many biological processes. MAT2A is up regulated in many cancers, including liver cancer and colorectal cancer (CRC) and is a potentially important drug target We developed a family of fluorinated N,N-dialkylaminostilbene agents, called FIDAS agents, that inhibit the proliferation of CRC cells in vitro and in vivo. Using a biotinylated FIDAS analogue, we identified the catalytic subunit of MAT2A as the direct and exclusive binding target of these FIDAS agents. MAT2B, an associated regulatory subunit of MAT2A, binds indirectly to FIDAS agents through its association with MAT2A. FIDAS agents inhibited MAT2A activity in SAM synthesis, and depletion of MAT'2A by shRNAs inhibited CRC cell growth A novel FIDAS agent delivered orally repressed CRC xenografts in athymic nude mice. These findings suggest that FIDAS analogues targeting MAT2A represent a family of novel and potentially useful agents for cancer treatment.
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