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

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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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Acknowledgments

This work was supported by the National Institutes of Health (RO1 CA152314, to R.M.W and J.E.B.). J.E.B. acknowledges support by Grants from the National Cancer Institute (1K08CA128972) and the Burroughs-Wellcome Foundation (CAMS). JLP acknowledges support from the State of Colorado Bioscience Development Program Grant. This work was also supported by University of Colorado Cancer Center Shared Resource (Pharmacology) support Grant (P30CA046934).

Conflict of interest

J.L.P. and R.M.W. are co-founders of Cetya Therapeutics, Inc.

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Authors and Affiliations

  1. Cetya Therapeutics, 1301 Center Avenue, Fort Collins, CO, 80523, USA

    John L. Pilon

  2. Flint Animal Cancer Center, Colorado State University, 300 West Drake Road, Fort Collins, CO, 80523, USA

    Ryan J. Hansen, Paul J. Lunghofer, Brad Charles, Barbara J. Rose, Douglas H. Thamm & Daniel L. Gustafson

  3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA

    James E. Bradner

  4. Department of Chemistry, Colorado State University, 1301 Center Avenue, Fort Collins, CO, 80523, USA

    Dane J. Clausen & Robert M. Williams

  5. University of Colorado Cancer Center, Aurora, CO, 80045, USA

    Douglas H. Thamm, Daniel L. Gustafson & Robert M. Williams

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  1. John L. Pilon
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Corresponding author

Correspondence to Robert M. Williams.

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Supplementary material 1 (PDF 242 kb)

280_2015_2675_MOESM2_ESM.docx

Plasma time-concentration curves for largazole and largazole peptide isostere. There was a significant difference between the curves as assessed by 2-way ANOVA (p = 0.0121). Error bars indicate standard deviation of the mean (DOCX 82 kb)

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Pilon, J.L., Clausen, D.J., Hansen, R.J. et al. Comparative pharmacokinetic properties and antitumor activity of the marine HDACi Largazole and Largazole peptide isostere. Cancer Chemother Pharmacol 75, 671–682 (2015). https://doi.org/10.1007/s00280-015-2675-1

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  • DOI: https://doi.org/10.1007/s00280-015-2675-1

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