Discovery of Novel Class I Histone Deacetylase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities

A successful structure-based design
of novel cyclic depsipeptides
that selectively target class I HDAC isoforms is described. Compound 11 has an IC50 of 2.78 nM for binding to the HDAC1
protein, and the prodrugs 12 and 13 also
exhibit promising antiproliferative activities in the nanomolar range
against various cancer cell lines. Compounds 12 and 13 show more than 20-fold selectivity toward human cancer
cells over human normal cells in comparison with romidepsin (FK228),
demonstrating low probability of toxic side effects. In addition,
compound 13 exhibits excellent in vivo anticancer activities in a human prostate carcinoma (Du145) xenograft
model with no observed toxicity. Thus, prodrug 13 has
therapeutic potential as a new class of anticancer agent for further
clinical translation.