1 research outputs found
Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties
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