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Preclinical Studies of YK-4-272, an Inhibitor of Class II Histone Deacetylases by Disruption of Nucleocytoplasmic Shuttling

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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.

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Abbreviations

AMMC:

3-[2-(N,N-diehtyl-N-methylamino)ethyl]-7-methoxy-4-methylcoumarin

BQ:

7-benzoyloxyquinoline

CEC:

3-cyano-7-ethoxycoumarin

CYP450:

Cytochrome P450

MFC:

7-methoxy-4-triflouromethylcoumarin

MRP:

multidrug resistance-associated protein

P-gp:

P-glycoprotein

TEER:

transepithelial electrical resistance

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ACKNOWLEDGMENTS AND DISCLOSURES

We thank Youngmi Kim, Yunjin Jung, and Mikell Paige for helpful discussions and technical assistance. This study was supported by National Institutes of Health grants (NIH/NCI P30 CA51008).

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Authors and Affiliations

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

    Hye-Sik Kong, Yali Kong, Li Zhang, Mira Jung, Anatoly Dritschilo & Milton L. Brown

  2. Drug Discovery Program, Georgetown University Medical Center, 3970 Reservoir Road, Washington, District of Colombia, 20057, USA

    Hye-Sik Kong, Yali Kong, Li Zhang & Milton L. Brown

  3. Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road, Washington, District of Colombia, 20057, USA

    Mira Jung & Anatoly Dritschilo

  4. Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China

    Shuo Tian & Guanhua Du

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  1. Hye-Sik Kong
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  2. Shuo Tian
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  3. Yali Kong
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Corresponding author

Correspondence to Milton L. Brown.

Additional information

Hye-Sik Kong and Shuo Tian contributed equally to this publication.

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Kong, HS., Tian, S., Kong, Y. et al. Preclinical Studies of YK-4-272, an Inhibitor of Class II Histone Deacetylases by Disruption of Nucleocytoplasmic Shuttling. Pharm Res 29, 3373–3383 (2012). https://doi.org/10.1007/s11095-012-0832-3

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  • DOI: https://doi.org/10.1007/s11095-012-0832-3

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