Discovery of Novel Class I Histone Deacetylase Inhibitors
with Promising in Vitro and in Vivo Antitumor Activities
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Abstract
A successful structure-based design
of novel cyclic depsipeptides
that selectively target class I HDAC isoforms is described. Compound <b>11</b> has an IC<sub>50</sub> of 2.78 nM for binding to the HDAC1
protein, and the prodrugs <b>12</b> and <b>13</b> also
exhibit promising antiproliferative activities in the nanomolar range
against various cancer cell lines. Compounds <b>12</b> and <b>13</b> 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 <b>13</b> exhibits excellent in vivo anticancer activities in a human prostate carcinoma (Du145) xenograft
model with no observed toxicity. Thus, prodrug <b>13</b> has
therapeutic potential as a new class of anticancer agent for further
clinical translation