Fluorinated N, N-dialkylaminostilbenes repress colon cancer by targeting methionine S-Adenosyltransferase 2A

Wen Zhang, Vitaliy Sviripa, Xi Chen, Jiandang Shi, Tianxin Yu, Adel Hamza, Nicholas D. Ward, Liliia M. Kril, Craig W. Vander Kooi, Chang Guo Zhan, B. Mark Evers, David S. Watt, Chunming Liu

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

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 MAT2A 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.

Original languageEnglish
Pages (from-to)796-803
Number of pages8
JournalACS Chemical Biology
Volume8
Issue number4
DOIs
StatePublished - Apr 19 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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