6096
J. E. Payne et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6093–6096
orally QOD in a 14-day xenograft, KD5170 demonstrated signifi-
cant tumor growth inhibition at 42 and 84 mg/kg with T/C values16
of 44% and 25%, respectively.
In summary, we have identified KD5170, a novel mercaptoke-
tone-based broad spectrum Class I and II-HDAC inhibitor with
potent activity in cell based assays that monitor histone acetyla-
tion, and broad spectrum activity against a variety of human tu-
mor cell lines. KD5170 exhibits high aqueous solubility and
when dosed orally or intravenously, gave a robust and sustained
pharmacodynamic response as monitored by histone H3 hyper-
acetylation in xenograft tumors. This robust pharmacodynamnic
response translated into tumor growth inhibition with chronic
oral administration of nude mice bearing HCT-116 xenograft tu-
mors. These data and others support the continued pre-clinical and
clinical development of KD5170 as an oncology therapeutic with po-
tential across a wide range of cancer indications.
Figure 3. KD5170 induces a robust and sustained pharmacodynamic response in
xenograft tumor tissues.
References and notes
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Figure 4. KD-5170 demonstrates tumor growth regression in HCT-116 tumor
bearing mice (po dosing).
dosing route was examined and gave a similar robust pharmacody-
namic response (12-fold over control).
12. The binding mode of the mercaptoketone maybe mono- or bi-dentate:
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The time course of histone H3 hyperacetylation in HCT-116 tu-
mors was also examined as shown in Figure 3. Following a 30 mg/
kg oral dose of KD5170, tumor H3 hyperacetylation rapidly in-
creased to reach a maximum at 4 h. Significant hyperacetylation
was also observed at 8 hours with levels decreasing by 24 h
(although still above T0 levels).
Finally, having demonstrated a sustained pharmacodynamic re-
sponse, KD5170 was examined for its anti-tumor potential in HCT-
116 tumor bearing nude mice. As shown in Figure 4, when dosed
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15. The cytotoxic activities (EC50) ranged from 0.1 to 7.7
median of 1.6 and 0.9 M, respectively.
lM with a mean and
l
16. T/C: (Treated final volume À Treated initial volume)/(Control final
volume À Control initial volume) Â 100.
A T/C value of 0 equals tumor
stasis.