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Preclinical Characterization of 3β-(N-Acetyl <scp>l</scp>-cysteine methyl ester)-2aβ,3-dihydrogaliellalactone (GPA512), a Prodrug of a Direct STAT3 Inhibitor for the Treatment of Prostate Cancer
- Source :
- Journal of Medicinal Chemistry. 59:4551-4562
- Publication Year :
- 2016
- Publisher :
- American Chemical Society (ACS), 2016.
-
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.
- Subjects :
- Male
Models, Molecular
STAT3 Transcription Factor
0301 basic medicine
Mice, Nude
Antineoplastic Agents
Pharmacology
Acetylcysteine
Mice
Structure-Activity Relationship
03 medical and health sciences
Prostate cancer
0302 clinical medicine
DU145
Pharmacokinetics
Oral administration
Drug Discovery
Tumor Cells, Cultured
medicine
Animals
Humans
Prodrugs
STAT3
Cell Proliferation
Dose-Response Relationship, Drug
Molecular Structure
biology
Chemistry
Prostatic Neoplasms
Neoplasms, Experimental
Prodrug
medicine.disease
In vitro
030104 developmental biology
030220 oncology & carcinogenesis
biology.protein
Molecular Medicine
Drug Screening Assays, Antitumor
medicine.drug
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 59
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....dbb402425066fb4bb747cbda6ea56bfb