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Pharm Res. 2012 Dec;29(12):3373-83. doi: 10.1007/s11095-012-0832-3. Epub 2012 Jul 27.

Preclinical studies of YK-4-272, an inhibitor of class II histone deacetylases by disruption of nucleocytoplasmic shuttling.

Author information

1
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road, Washington, District of Colombia 20057, USA.

Abstract

PURPOSE:

The HDAC shuttling inhibitor, YK-4-272 functions by restricting nuclear shuttling of Class II HDACs. Pre-clinical investigations of YK-4-272 bioavailability, pharmacokinetics, in vivo toxicity and tumor growth inhibition were performed to determine its potential as an HDAC shuttling disruptor for use in clinical applications.

METHODS:

The solubility, lipophilicity, in vitro metabolic stability, in vitro intestinal permeability, and in vivo pharmacokinetics of YK-4-272 were determined by HPLC methods. The anti-tumor activity of YK-4-272 was determined by monitoring athymic Balb/c nude mice bearing PC-3 xenografts.

RESULTS:

Oral bioavailability of YK-4-272 is supported by its solubility (0.537 mg/mL) and apparent partition coefficient of 2.0. The compound was chemically and metabolically stable and not a substrate for CYP450. In Caco-2 cell transport studies, YK-4-272 was highly permeable. The time-concentration profile of YK-4-272 in plasma resulted in a C ( max ) of 2.47 μg/mL at 0.25 h with a AUC of 3.304 μg × h/mL. Treatment of PC-3 tumor xenografts with YK-4-272 showed significant growth delay.

CONCLUSIONS:

YK-4-272 is stable and bio-available following oral administration. Growth inhibition of cancer cells and tumors was observed. These studies support advancing YK-4-272 for further evaluation as a novel HDAC shuttling inhibitor for use in cancer treatment.

PMID:
22836184
PMCID:
PMC4111571
DOI:
10.1007/s11095-012-0832-3
[Indexed for MEDLINE]
Free PMC Article

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