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Preclinical Characterization of 3β-(N-Acetyl l -cysteine methyl ester)-2aβ,3-dihydrogaliellalactone (GPA512), a Prodrug of a Direct STAT3 Inhibitor for the Treatment of Prostate Cancer

  • Zilma Escobar
  • Anders Bjartell
  • Giacomo Canesin
  • Susan Evans-Axelsson
  • Olov Sterner
  • Rebecka Hellsten
  • Martin H. Johansson
Publishing year: 2016-05-26
Language: English
Pages: 4551-4562
Publication/Series: Journal of Medicinal Chemistry
Volume: 59
Issue: 10
Document type: Journal article
Publisher: American Chemical Society (ACS)

Abstract english

The transcription factor STAT3 is a potential target for the treatment of castration-resistant prostate cancer. Galiellalactone (1), a direct inhibitor of STAT3, prevents the transcription of STAT3 regulated genes. In this study we characterized 6 (GPA512, Johansson, M.; Sterner, O. Patent WO 2015/132396 A1, 2015), a prodrug of 1. In vitro studies showed that 6 is rapidly converted to 1 in plasma and is stable in a buffer solution. The pharmacokinetics of 6 following a single oral dose indicated that the prodrug was rapidly absorbed and converted to 1 with a tmax of 15 min. Oral administration of 6 in mice increased the plasma exposure of the active parent compound 20-fold compared to when 1 was dosed orally. 6 treated mice bearing DU145 xenograft tumors had significantly reduced tumor growth compared to untreated mice. The favorable druglike properties and safety profile of 6 warrant further studies of 6 for the treatment of castration-resistant prostate cancer.


  • Cancer and Oncology


  • Urological cancer, Malmö
  • ISSN: 0022-2623
Olov Sterner
E-mail: olov [dot] sterner [at] science [dot] lu [dot] se


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