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
Författare
Summary, in 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.
Avdelning/ar
- Centrum för analys och syntes
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- Urologisk cancerforskning, Malmö
- EpiHealth: Epidemiology for Health
Publiceringsår
2016-05-26
Språk
Engelska
Sidor
4551-4562
Publikation/Tidskrift/Serie
Journal of Medicinal Chemistry
Volym
59
Issue
10
Dokumenttyp
Artikel i tidskrift
Förlag
The American Chemical Society (ACS)
Ämne
- Cancer and Oncology
Status
Published
Forskningsgrupp
- Urological cancer, Malmö
ISBN/ISSN/Övrigt
- ISSN: 0022-2623