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

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.

• Authors: 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
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 75 Issue 4 Pg. 671-82 (Apr 2015) ISSN: 1432-0843 [Electronic] Germany
• PMID: 25616967 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Depsipeptides
• Histone Deacetylase Inhibitors
• Pyridines
• Thiazoles
• largazole

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology)
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Depsipeptides (chemistry, pharmacokinetics, pharmacology)
• Dose-Response Relationship, Drug
• Female
• Histone Deacetylase Inhibitors (chemistry, pharmacokinetics, pharmacology)
• Humans
• Kaplan-Meier Estimate
• Lung Neoplasms (drug therapy)
• Mice
• Mice, Nude
• Models, Biological
• Molecular Structure
• Pyridines (chemistry, pharmacology)
• Structure-Activity Relationship
• Thiazoles (chemistry, pharmacokinetics, pharmacology)
• Xenograft Model Antitumor Assays