Histone deacetylase (
HDAC) inhibitors have garnered significant attention as
cancer drugs. These therapeutic agents have recently been clinically validated with the market approval of
vorinostat (SAHA,
Zolinza) for treatment of
cutaneous T-cell lymphoma. Like
vorinostat, most of the small-molecule
HDAC inhibitors in clinical development are
hydroxamic acids, whose inhibitory activity stems from their ability to coordinate the catalytic Zn2+ in the active site of HDACs. We sought to identify novel, nonhydroxamate-based
HDAC inhibitors with potentially distinct
pharmaceutical properties via an ultra-high throughput small molecule biochemical screen against the HDAC activity in a HeLa cell nuclear extract. An alpha-mercaptoketone series was identified and chemically optimized. The lead compound,
KD5170, exhibits HDAC inhibitory activity with an IC50 of 0.045 micromol/L in the screening biochemical assay and an EC50 of 0.025 micromol/L in HeLa cell-based assays that monitor
histone H3 acetylation.
KD5170 also exhibits broad spectrum classes I and II HDAC inhibition in assays using purified recombinant human
isoforms.
KD5170 shows significant antiproliferative activity against a variety of human tumor cell lines, including the NCI-60 panel. Significant
tumor growth inhibition was observed after p.o. dosing in human HCT-116 (
colorectal cancer), NCI-H460 (
non-small cell lung carcinoma), and PC-3 (
prostate cancer) s.c. xenografts in nude mice. In addition, a significant increase in antitumor activity and time to end-point occurred when
KD5170 was combined with
docetaxel in xenografts of the PC-3
prostate cancer cell line. The
biological and
pharmaceutical profile of
KD5170 supports its continued preclinical and clinical development as a broad spectrum
anticancer agent.