Small Molecule Inhibitors of Class Two Histone Deacetylases (HDAC)

Categories: "Cancer Therapeutics"

Reference #: 2007-007

OTC Contact: Ruchika Nijhara, Ph.D., MBA, CLP, Director ( Directory Information | Send a Message )

Description

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. 

Applications

  • Therapeutic for the treatment of cancers such as lymphomas, leukemias, breast, lung and prostate
  • ​Diagnostic/research tool due to the presence of a fluorescent moiety

Advantages

  • Novel mechanism distinct from currently approved HDAC inhibitors
  • Effective at concentrations similar to approved HDAC inhibitors
  • Advanced preclinical development stage, including toxicity studies in animal models
  • Fluorescently labeled so that inhibitor can be visualized

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

Inventors

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