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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

Escobar, Zilma LU ; Bjartell, Anders LU ; Canesin, Giacomo LU ; Evans-Axelsson, Susan LU orcid ; Sterner, Olov LU ; Hellsten, Rebecka LU and Johansson, Martin H. (2016) In Journal of Medicinal Chemistry 59(10). p.4551-4562
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... (More)

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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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
59
issue
10
pages
12 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • wos:000376840600011
  • pmid:27111731
  • scopus:84971611840
ISSN
0022-2623
DOI
10.1021/acs.jmedchem.5b01814
language
English
LU publication?
yes
id
1280cc42-c827-4883-803f-95ad4f175ddd
date added to LUP
2016-07-04 09:56:18
date last changed
2025-01-12 08:27:39
@article{1280cc42-c827-4883-803f-95ad4f175ddd,
  abstract     = {{<p>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<sub>max</sub> 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.</p>}},
  author       = {{Escobar, Zilma and Bjartell, Anders and Canesin, Giacomo and Evans-Axelsson, Susan and Sterner, Olov and Hellsten, Rebecka and Johansson, Martin H.}},
  issn         = {{0022-2623}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{10}},
  pages        = {{4551--4562}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Medicinal Chemistry}},
  title        = {{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}},
  url          = {{http://dx.doi.org/10.1021/acs.jmedchem.5b01814}},
  doi          = {{10.1021/acs.jmedchem.5b01814}},
  volume       = {{59}},
  year         = {{2016}},
}