Blockade of STAT3 activation by sorafenib derivatives through enhancing SHP-1 phosphatase activity

Eur J Med Chem. 2012 Sep;55:220-7. doi: 10.1016/j.ejmech.2012.07.023. Epub 2012 Jul 23.

Abstract

Previously, we demonstrated that the multiple kinase inhibitor sorafenib mediates the repression of phospho-STAT3 in hepatocellular carcinoma cells. In this study, we used this kinase-independent mechanism as a molecular basis to use sorafenib as scaffold to develop a novel class of SHP-1-activating agents. The proof of principle of this premise was provided by SC-1, which on replacement of N-methylpicolinamide by a phenylcyano group showed abolished kinase activity while retaining phospho-STAT3 repressive activity. Structural optimization of SC-1 led to compound 6, which repressed phospho-STAT3 through SHP-1 activation and inhibited PLC5 cell proliferation at sub-micromolar potency. In light of the pivotal role of phospho-STAT3 in promoting tumorigenesis and drug resistance, this novel SHP-1-activating agent may have therapeutic relevance in cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzenesulfonates / chemistry*
  • Benzenesulfonates / pharmacology*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Phosphoproteins / metabolism
  • Protein Kinase Inhibitors / analogs & derivatives*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
  • Pyridines / chemistry*
  • Pyridines / pharmacology*
  • STAT3 Transcription Factor / metabolism*
  • Sorafenib
  • Xenograft Model Antitumor Assays

Substances

  • Benzenesulfonates
  • Phenylurea Compounds
  • Phosphoproteins
  • Protein Kinase Inhibitors
  • Pyridines
  • STAT3 Transcription Factor
  • Niacinamide
  • Sorafenib
  • Protein Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6