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@ARTICLE{Stafford:132562,
      author       = {W. C. Stafford and X. Peng and M. H. Olofsson and X. Zhang
                      and D. K. Luci and L. Lu and Q. Cheng and L. Trésaugues and
                      T. S. Dexheimer and N. P. Coussens and M. Augsten$^*$ and H.
                      M. Ahlzén and O. Orwar and A. Östman and S. Stone-Elander
                      and D. J. Maloney and A. Jadhav and A. Simeonov and S.
                      Linder and E. S. J. Arnér},
      title        = {{I}rreversible inhibition of cytosolic thioredoxin
                      reductase 1 as a mechanistic basis for anticancer therapy.},
      journal      = {Science translational medicine},
      volume       = {10},
      number       = {428},
      issn         = {1946-6242},
      address      = {Washington, DC},
      publisher    = {AAAS},
      reportid     = {DKFZ-2018-00240},
      pages        = {eaaf7444 -},
      year         = {2018},
      abstract     = {Cancer cells adapt to their inherently increased oxidative
                      stress through activation of the glutathione (GSH) and
                      thioredoxin (TXN) systems. Inhibition of both of these
                      systems effectively kills cancer cells, but such broad
                      inhibition of antioxidant activity also kills normal cells,
                      which is highly unwanted in a clinical setting. We therefore
                      evaluated targeting of the TXN pathway alone and, more
                      specifically, selective inhibition of the cytosolic
                      selenocysteine-containing enzyme TXN reductase 1 (TXNRD1).
                      TXNRD1 inhibitors were discovered in a large screening
                      effort and displayed increased specificity compared to
                      pan-TXNRD inhibitors, such as auranofin, that also inhibit
                      the mitochondrial enzyme TXNRD2 and additional targets. For
                      our lead compounds, TXNRD1 inhibition correlated with cancer
                      cell cytotoxicity, and inhibitor-triggered conversion of
                      TXNRD1 from an antioxidant to a pro-oxidant enzyme
                      correlated with corresponding increases in cellular
                      production of H2O2In mice, the most specific TXNRD1
                      inhibitor, here described as TXNRD1 inhibitor 1 (TRi-1),
                      impaired growth and viability of human tumor xenografts and
                      syngeneic mouse tumors while having little mitochondrial
                      toxicity and being better tolerated than auranofin. These
                      results display the therapeutic anticancer potential of
                      irreversibly targeting cytosolic TXNRD1 using small
                      molecules and present potent and selective TXNRD1
                      inhibitors. Given the pronounced up-regulation of TXNRD1 in
                      several metastatic malignancies, it seems worthwhile to
                      further explore the potential benefit of specific
                      irreversible TXNRD1 inhibitors for anticancer therapy.},
      cin          = {A190},
      ddc          = {500},
      cid          = {I:(DE-He78)A190-20160331},
      pnm          = {311 - Signalling pathways, cell and tumor biology
                      (POF3-311)},
      pid          = {G:(DE-HGF)POF3-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29444979},
      doi          = {10.1126/scitranslmed.aaf7444},
      url          = {https://inrepo02.dkfz.de/record/132562},
}