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Cited by 27Histone Deacetylase Inhibitors ResearchEnzyme function and inhibitionSynthesis and biological activity

Pharmacokinetics–pharmacodynamics and antitumor activity of mercaptoacetamide-based histone deacetylase inhibitors

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Konsoula, Zacharoula, Cao, Hong, Velena, Alfredo, Jung, Mira·2009·Molecular Cancer Therapeutics
DOI 10.1158/1535-7163.mct-09-0629PMC PMC3711100

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Abstract

Structurally diverse histone deacetylase inhibitors (HDACI) have emerged as chemotherapeutic agents. Here, we report the first mercaptoacetamide HDACIs (coded 6MAQH and 5MABMA) for use in treatment against prostate cancer cells in vitro and in vivo and correlate their plasma pharmacokinetics and tissue-pharmacodynamics with tumor sensitivity. HDACIs were assessed for in vitro microsomal stability and growth inhibition against prostate cancer and nonmalignant cells. Antitumor activity was determined following i.p. administration of 6MAQH and 5MABMA (0.5 and 5 mg/Kg) using mice bearing PC3 tumor xenografts (n = 10). The plasma pharmacokinetics of 6MAQH and 5MABMA and their effects on the acetylation of histone H4 in tissues were determined in athymic mice. Both HDACIs significantly inhibited the growth of cancer cells while exerting limited effect on nonmalignant cells. They exhibited stability in human, dog, and rat microsomes [t1/2 (min) = 83, 72, and 66 for 6MAQH and 68, 43, and 70 for 5MABMA, respectively]. Both HDACIs (0.5 mg/Kg) led to tumor regression (P < 0.01), which was sustained for at least 60 days. In vivo data show favorable plasma pharmacokinetics with the area under the curve of 4.97 ± 0.6 μmol/L × h for 6MAQH and 4.23 ± 0.43 μmol/L × h for 5MABMA. The clearance rates for 6MAQH and 5MABMA were 4.05 ± 0.15 and 4.87 ± 0.2 L/h, whereas the half-lives were 2.2 ± 0.33 and 1.98 ± 0.21 h, respectively. Both HDACIs markedly enhanced the acetylation of histone H4 within 30 minutes in tissues, including the brain, liver, and spleen. Taken together, the results provide a rationale for further investigation of these mercaptoacetamide HDACIs as potent anticancer agents. [Mol Cancer Ther 2009;8(10):2844–51]

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  • The novel HDAC inhibitors W2 (mercaptoacetamide-based class II) and I2 (hydroxamide-based class I and II) have improved pharmacological properties, including longer half-life and greater blood-brain barrier penetration, compared to commercially available HDACIs.

    “We developed two novel HDAC inhibitors with improved pharmacological properties, such as a longer half-life and greater penetration of the blood-brain barrier: mercaptoacetamide-based class II HDACI (coded as W2) and hydroxamide-based class I and IIHDACI (coded as I2)”

    From Mercaptoacetamide-based class II HDAC inhibitor lowers Aβ levels and improves learning and memory in a mouse model of Alzheimer's disease (2013) · cites this paper as Konsoula, et al., 2009

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Authors
Konsoula, Z., Cao, H., Velena, A., & Jung, M.
Affiliations
Georgetown University Medical Center (US)
Corresponding author
Jung, Mira
ORCID
Venue
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research (AACR)
Published
2009-10-01
Volume
8
Issue
10
Pages
2844-2851
ISSN
  • 1535-7163 (ISSN-L)
  • 1538-8514
DOI
10.1158/1535-7163.mct-09-0629
PMC
PMC3711100
OpenAlex
W2132983060
Cited by
27
References
2
Citations by year
2026: 1 · 2025: 4 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 5 · 2018: 3 · 2016: 2 · 2015: 1 · 2014: 2 · 2013: 1 · 2012: 1
FWCI
0.54
Type
journal article
Language
en
Open access
Locations
  • Molecular Cancer Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (P01CA074175)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
Keywords
histone deacetylase inhibitors, pharmacokinetics, pharmacodynamics, anticancer activity, prostate cancer, histone H4 acetylation, microsomal stability, tumor xenografts, PC-3 cells, drug clearance
MeSH terms
Acetamides, Animals, Antineoplastic Agents, Dogs, Drug Screening Assays, Antitumor, Drug Stability, Humans, Male, Prostatic Neoplasms, Thioglycolates, Time Factors, Maximum Tolerated Dose, Cell Line, Tumor, Cell Proliferation, Mice, Rats, Histone Deacetylase Inhibitors

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