Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties.
Published
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
- 25147612
Electronic International Standard Serial Number (EISSN)
- 1948-5875
International Standard Serial Number (ISSN)
- 1948-5875
Digital Object Identifier (DOI)
- 10.1021/ml500170r
Language
- eng