PCI-34051

PCI-34051 possesses promising potency for HDAC8 with a K_i of 10 nM. PCI-34051 has high selectivity (approximately fivefold) for HDAC8 relative to the other class I HDACs including HDAC1. PCI-34051 reveals greater than 200-fold selectivity over HDAC1 and HDAC6, and greater than 1000-fold selectivity over HDAC2, HDAC3 and HDAC10. PCI-34051 inhibits ovarian tumor line OVCAR-3 with a GI50 of 6 μM and 15% cell death. Neither significant tubulin nor histone acetylation is observed in the sensitive cell lines treated with PCI-34051 at concentrations less than 25 μM at 24 hours nor at earlier timepoints. PCI-34051 induces a selective cytotoxic effect in cell lines derived only from T-cell malignancies. PCI-34051 induces caspase-dependent apoptosis. When caspase-3 activity is measured at various times after treatment with 5 μM PCI-34051, increasing levels of activity are observed from 12 to 24 to 48 hours, another hallmark of apoptosis, consistent with the higher levels of caspase activity at this timepoint. PCI-34051 does not stimulate Bid cleavage, a characteristic effect of the extrinsic apoptotic pathway. While P116 and J.RT3-T.5 are sensitive to PCI-34051, the PLCγ1-deficient J.gamma1 line reveals a marked decrease in the extent of PCI-34051-induced apoptosis. In addition, steady-state calcium levels strongly influence the apoptosis induced by PCI-34051. PCI-34051 induces cytochrome c release from mitochondria.^[1]