2. Academic Validation
  3. 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

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

  • J Med Chem. 2016 May 26;59(10):4551-62. doi: 10.1021/acs.jmedchem.5b01814.
Zilma Escobar 1,  Anders Bjartell 2,  Giacomo Canesin 2,  Susan Evans-Axelsson 2,  Olov Sterner 1,  Rebecka Hellsten 2,  Martin H Johansson 3
Affiliations

Affiliations

  • 1 Center for Analysis and Synthesis, Lund University , SE-221 00 Lund, Sweden.
  • 2 Division of Urological Cancers, Department of Translational Medicine, Lund University , SE-205 02 Malmo, Sweden.
  • 3 Glactone Pharma Development AB , SE-252 20 Helsingborg, Sweden.
PMID: 27111731 DOI: 10.1021/acs.jmedchem.5b01814
Abstract

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.

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