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.
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.
Center for Analysis and Synthesis, Lund University , SE-221 00 Lund, Sweden.
Zilma
Z
Escobar
Division of Urological Cancers, Department of Translational Medicine, Lund University , SE-205 02 Malmo, Sweden.
Anders
A
Bjartell
Division of Urological Cancers, Department of Translational Medicine, Lund University , SE-205 02 Malmo, Sweden.
Giacomo
G
Canesin
Division of Urological Cancers, Department of Translational Medicine, Lund University , SE-205 02 Malmo, Sweden.
Susan
S
Evans-Axelsson
Center for Analysis and Synthesis, Lund University , SE-221 00 Lund, Sweden.
Olov
O
Sterner
Division of Urological Cancers, Department of Translational Medicine, Lund University , SE-205 02 Malmo, Sweden.
Rebecka
R
Hellsten
Glactone Pharma Development AB , SE-252 20 Helsingborg, Sweden.
Martin H
MH
Johansson
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C000619424:GPA512; D011355:Prodrugs; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000111:Acetylcysteine