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

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 t_max 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.

• Author: Zilma Escobar; Anders Bjartell; Giacomo Canesin; Susan Evans-Axelsson; Olov Sterner; Rebecka Hellsten; Martin H. Johansson
• Department/s: Centre for Analysis and Synthesis; BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation; Urological cancer, Malmö; EpiHealth: Epidemiology for Health
• Publishing year: 2016-05-26
• Language: English
• Pages: 4551-4562
• Publication/Series: Journal of Medicinal Chemistry
• Volume: 59
• Issue: 10
• Links: http://dx.doi.org/10.1021/acs.jmedchem.5b01814
• Document type: Journal article
• Publisher: The American Chemical Society (ACS)
• Topic: Cancer and Oncology
• Status: Published
• Research group: Urological cancer, Malmö
• ISBN/ISSN/Other: ISSN: 0022-2623