2. Academic Validation
  3. Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death

Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death

  • Sci Adv. 2020 Mar 20;6(12):eaax7945. doi: 10.1126/sciadv.aax7945.
S Busker 1,  W Qian 2,  M Haraldsson 3,  B Espinosa 1,  L Johansson 3,  S Attarha 4,  I Kolosenko 5,  J Liu 6,  M Dagnell 1,  D Grandér 5,  E S J Arnér 1,  K Pokrovskaja Tamm 5,  B D G Page 4 7
Affiliations

Affiliations

  • 1 Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • 2 Laboratories for Chemical Biology Umeå, Chemical Biology Consortium Sweden, Umeå University, Umeå, Sweden.
  • 3 Chemical Biology Consortium Sweden, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • 4 Department of Oncology and Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
  • 5 Department of Oncology and Pathology, Bioclinicum, Karolinska Institutet, Stockholm, Sweden.
  • 6 Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
  • 7 Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
PMID: 32219156 DOI: 10.1126/sciadv.aax7945
Abstract

Because of its key role in Cancer development and progression, STAT3 has become an attractive target for developing new Cancer therapeutics. While several STAT3 inhibitors have progressed to advanced stages of development, their underlying biology and mechanisms of action are often more complex than would be expected from specific binding to STAT3. Here, we have identified and optimized a series of compounds that block STAT3-dependent luciferase expression with nanomolar potency. Unexpectedly, our lead compounds did not bind to cellular STAT3 but to another prominent Anticancer drug target, TrxR1. We further identified that TrxR1 inhibition induced Prx2 and STAT3 oxidation, which subsequently blocked STAT3-dependent transcription. Moreover, previously identified inhibitors of STAT3 were also found to inhibit TrxR1, and likewise, established TrxR1 inhibitors block STAT3-dependent transcriptional activity. These results provide new insights into the complexities of STAT3 redox regulation while highlighting a novel mechanism to block aberrant STAT3 signaling in Cancer cells.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-153902
    STAT3-dependent, transcription, probe, dansyl