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      Inhibiting aberrant signal transducer and activator of transcription protein activation with tetrapodal, small molecule Src homology 2 domain binders: promising agents against multiple myeloma.

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          Abstract

          The signal transducer and activator of transcription (STAT) proteins represent a family of cytoplasmic transcription factors that regulate a pleiotropic range of biological processes. In particular, Stat3 protein has attracted attention as it regulates the expression of genes involved in a variety of malignant processes, including proliferation, survival, migration, and drug resistance. Multiple myeloma (MM) is an incurable hematologic malignancy that often exhibits abnormally high levels of Stat3 activity. Although current treatment strategies can improve the clinical management of MM, it remains uniformly incurable with a dismal median survival time post-treatment of 3-4 years. Thus, novel targeted therapeutics are critically needed to improve MM patient outcomes. We herein report the development of a series of small molecule Stat3 inhibitors with potent anti-MM activity in vitro. These compounds showed high-affinity binding to Stat3's SH2 domain, inhibited intracellular Stat3 phosphorylation, and induced apoptosis in MM cell lines at low micromolar concentrations.

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          Author and article information

          Journal
          J. Med. Chem.
          Journal of medicinal chemistry
          1520-4804
          0022-2623
          Sep 26 2013
          : 56
          : 18
          Affiliations
          [1 ] Department of Chemical and Physical Sciences, University of Toronto Mississauga , 3359 Mississauga Road, Mississauga, Ontario, Canada L5L 1C6.
          Article
          10.1021/jm3017255
          23968501

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