Small Molecule Inhibitors of Class Two Histone Deacetylases (HDAC)

Categories: “Cancer Therapeutics

Reference #: 2007-007

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Histone deacetylase inhibitors (HDAC inhibitors) have emerged as an effective class of drugs for a wide range of cancers. This is due to the importance of histone deacetylation in the maintenance of chromatin structure, which has an effect on gene expression, and on protein function. Elevated expression of HDAC proteins contributes to a less differentiated, more aggressive cancer phenotype.

Among the HDAC inhibitors both approved and under development, most target the catalytic domain, and are therefore effective at all four subtypes of HDACs. Researchers at Georgetown University have developed inhibitors specific for Class II HDACs that function by blocking the nuclear localization of Class II, thereby inhibiting the transcription repressing function of the proteins. These Class II HDAC “shuttling inhibitors” therefore represent a distinct class of HDAC inhibitors useful to treat cancer. The novel lead molecule has been evaluated for solubility, cell permeability, toxicity, ADME and in vivo efficacy. 



Stage of Development

Lead compounds have been evaluated for efficacy, toxicity, and pharmacodynamics in animal models

Patent Status

US Patent 8,293,513 filed June 20, 2010 and issued October 23, 2012

International applications – Pending

Relevant Publications

Kong Y, Jung M, Wang K, Grindrod S, Velena A, Lee SA, Dakshanamurthy S, Yang Y, Miessau M, Zheng C, Dritschilo A, Brown ML. “Histone deacetylase cytoplasmic trapping by a novel fluorescent HDAC inhibitor.”  Mol Cancer Ther. 2011 Sep;10(9):1591-9. PMID: 21697394

Kong HS, Tian S, Kong Y, Du G, Zhang L, Jung M, Dritschilo A, Brown ML. “Preclinical studies of YK-4-272, an inhibitor of class II histone deacetylases by disruption of nucleocytoplasmic shuttling.” Pharm Res. 2012 Dec;29(12):3373-83. PMID: 22836184


Milton L. Brown, Mira Jung, Anatoly Dritschilo, and Yali Kong