Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties.

Journal Article (Journal Article)

Largazole is a potent and class I-selective histone deacetylase (HDAC) inhibitor purified from marine cyanobacteria and was demonstrated to possess antitumor activity. Largazole employs a unique prodrug strategy, via a thioester moiety, to liberate the bioactive species largazole thiol. Here we report alternate prodrug strategies to modulate the pharmacokinetic and pharmacodynamics profiles of new largazole-based compounds. The in vitro effects of largazole analogues on cancer cell proliferation and enzymatic activities of purified HDACs were comparable to the natural product. However, in vitro and in vivo histone hyperacetylation in HCT116 cells and implanted tumors, respectively, showed differences, particularly in the onset of action and oral bioavailability. These results indicate that, by employing a different approach to disguise the "warhead" moiety, the functional consequence of these prodrugs can be significantly modulated. Our data corroborate the role of the pharmacokinetic properties of this class of compounds to elicit the desired and timely functional response.

Full Text

Duke Authors

Cited Authors

  • Salvador, LA; Park, H; Al-Awadhi, FH; Liu, Y; Kim, B; Zeller, SL; Chen, Q-Y; Hong, J; Luesch, H

Published Date

  • August 2014

Published In

Volume / Issue

  • 5 / 8

Start / End Page

  • 905 - 910

PubMed ID

  • 25147612

Pubmed Central ID

  • PMC4137384

Electronic International Standard Serial Number (EISSN)

  • 1948-5875

International Standard Serial Number (ISSN)

  • 1948-5875

Digital Object Identifier (DOI)

  • 10.1021/ml500170r


  • eng