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01.04.2015 | Original Article

Comparative pharmacokinetic properties and antitumor activity of the marine HDACi Largazole and Largazole peptide isostere

verfasst von: John L. Pilon, Dane J. Clausen, Ryan J. Hansen, Paul J. Lunghofer, Brad Charles, Barbara J. Rose, Douglas H. Thamm, Daniel L. Gustafson, James E. Bradner, Robert M. Williams

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2015

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Abstract

Purpose

Largazole is a potent class I-selective HDACi natural product isolated from the marine cyanobacteria Symploca sp. The purpose of this study was to test synthetic analogs of Largazole to identify potential scaffold structural modifications that would improve the drug-like properties of this clinically relevant natural product.

Methods

The impact of Largazole scaffold replacements on in vitro growth inhibition, cell cycle arrest, induction of apoptosis, pharmacokinetic properties, and in vivo activity using a xenograft model was investigated.

Results

In vitro studies in colon, lung, and pancreatic cancer cell lines showed that pyridyl-substituted Largazole analogs had low-nanomolar/high-picomolar antiproliferative activity, and induced apoptosis and cell cycle arrest at concentrations equivalent to or lower than the parent compound Largazole. Using IV bolus delivery at 5 mg/kg, two compartmental pharmacokinetic modeling on the peptide isostere analog of Largazole indicated improved pharmacokinetic parameters. In an A549 non-small cell lung carcinoma xenograft model using a dosage of 5 mg/kg administered intraperitoneally every other day, Largazole, Largazole thiol, and Largazole peptide isostere demonstrated tumor growth inhibition (TGI %) of 32, 44, and 66 %, respectively. Largazole peptide isostere treatment was statistically superior to control (p = 0.002) and to Largazole (p = 0.006). Surprisingly, tumor growth inhibition was not observed with the potent pyridyl-based analogs.

Conclusions

These results establish that replacing the depsipeptide linkage in Largazole with an amide may impart pharmacokinetic and therapeutic advantage and that alternative prodrug forms of Largazole are feasible.

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Titel: Comparative pharmacokinetic properties and antitumor activity of the marine HDACi Largazole and Largazole peptide isostere
verfasst von: John L. Pilon
Dane J. Clausen
Ryan J. Hansen
Paul J. Lunghofer
Brad Charles
Barbara J. Rose
Douglas H. Thamm
Daniel L. Gustafson
James E. Bradner
Robert M. Williams
Publikationsdatum: 01.04.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2015
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-015-2675-1

Springer Medizin

Comparative pharmacokinetic properties and antitumor activity of the marine HDACi Largazole and Largazole peptide isostere