Histone Deacetylase (HDAC) Inhibitors

Categories: “Neurological Disorders” “Cancer Therapeutics

Reference #: 2002-005 and 2005-014

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


Histone acetylation and deacetylation are important in chromatin folding and maintenance. HDACs are also involved in the reversible acetylation of non-histone proteins. Altered HDAC activities are present in many types of cancers and as a result are an attractive therapeutic target for drug discovery. Georgetown University is seeking a partner interested in the development and commercialization of novel HDAC inhibitors. Dr. Mira Jung and colleagues have discovered compounds and derivatives that are effective in sensitizing cancer cells as well as enhancing the cytotoxic effects of radiotherapy. The HDAC inhibitors may also be used for the treatment of neurodegenerative diseases. Several of the compounds show 50% HDAC inhibition at nanomolar concentrations.


This technology encompasses new pharmaceutical compositions that could be developed as potential agents for treatment of cancer and neurodegenerative diseases.


Stage of Development

Rational design was used to guide the synthesis of mercaptoacetamide and hydroxyamide-based compounds to be used as HDAC inhibitors. The compounds were tested on radiation-resistant cancer cell lines for the initial radiosensitization experiments. In cells pretreated with the compounds, the radiation dose required was decreased by 33% compared to non-treated controls. In vitro assays demonstrated that several of the compounds were effective and inhibiting 50% HDAC activity at low nanomolar concentrations. Administration of the representative compounds of each class led to tumor regression in mouse models.

Key experiments that need to be performed include: 1) testing the effects of the compounds, including toxicity and stability studies, in large animals and 2) determining compound efficacy on three additional cancer cell lines.

Relevant Publications

Chen B, Petukhov PA, Jung M, Velena A, Eliseeva E, Dritschilo A, Kozikowski AP. Chemistry and biology of mercaptoacetamides as novel histone histone deacetylase inhibitors. Bioorganic Medicinal Chemistry Letters, 15: 1389-1392, 2005.

Jung M, Velena A, Chen B, Petukhov PA, Kozikowski AP, Dritschilo A. Novel HDAC Inhibitors with Radiosensitizing Properties. Radiat Res, 163: 488-493, 2005.

Jung M, Kozikowski A, Dritschilo A. Rational Design and Development of Radiation-Sensitizing Histone Deacetylase Inhibitors. Chemistry and Biodiversity 2: 1452-1461, 2005.

Konsoula R and Jung M. In Vitro Plasma Stability, Permeability and Solubility of Mercaptoacetamide Histone Deacetylase Inhibitors. International Journal of Pharmaceutics, 361: 19-25, 2008.

Konsoula R and Jung M. Involvement of P-glycoprotein and multidrug resistance associated protein 1 in the transepithelial transport of a mercaptoacetamide-based histone-deacetylase inhibitor in Caco-2 cells. Biol Pharm Bull. 32: 74-78, 2009.

Agbor-Enoh S, Seudieu C, Davidson E, Dritschilo A and Jung M. A novel inhibitor of Plasmodium histone deacetylase that cures P. berghei-infected mice. Antimicrobial Agents and Chemotherapy 53: 1727-1734, 2009.

Jung M, Yong KJ, Velena A, Lee SA. Epigenetic Targets in Drug Discovery: Cell-based assays for HDAC inhibitor hit validation. The Wiley-VCH series “Methods and Principles in Medicinal Chemistry 42:119-137, 2009.

Alexander-Thomas Hauser AT, Jung M and Jung M. Review-Assays for Histone Deacetylases. Current Topics in Medicinal Chemistry 9: 227-234, 2009.

Konsoula Z, Cao H, Velena A, Jung M. Pharmacokinetics-pharmacodynamics and antitumor activity of mercaptoacetamide histone deacetylase inhibitors. Mole. Cancer Ther, 8: 2844-2851, 2009.

Tang H, Wang XS, Huang XP, Roth BL, Butler KV, Kozikowski AP, Jung M, Tropsha A. Novel Inhibitors of Human Histone Deacetylase (HDAC) Identified by QSAR Modeling of Known Inhibitors, Virtual Screening and Experimental Validation. Epub_ Journal of Chemical Information and Modeling. 2009.

Kozikowski AP, Chen Y, Gaysin AM, Savoy DN, Billadeau DD, and Kim KH. Chemistry, Biology, and QSAR Studies of Substituted Biaryl Hydroxamates and Mercaptoacetamides as HDAC Inhibitors—Nanomolar-Potency Inhibitors of Pancreatic Cancer Cell Growth. ChemMedChem 3: 487 – 501, 2008

Zhang B, West EJ, Van KC, Gurkoff GG, Zhou J, Zhang XM, Kozikowski AP, Lyeth BG. HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats. Brain Res. 1226:181-91, 2008.

Dow GS, Chen Y, Andrews KT, Caridha D, Gerena L, Gettayacamin M, Johnson J, Li Q, Melendez V, Obaldia N 3rd, Tran TN, Kozikowski AP. Antimalarial activity of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors. Antimicrob Agents Chemother. 52:3467-77, 2008.

Kozikowski AP, Chen Y, Gaysin AG, Chen B, D’Annibale MA, Suto CM, and Langley BC. Functional Differences in Epigenetic ModulatorssSuperiority of Mercaptoacetamide-Based Histone Deacetylase Inhibitors Relative to Hydroxamates in Cortical Neuron Neuroprotection Studies. J. Med. Chem. 50: 3054-3061, 2007.

Rivieccio MA, Brochier C, Willis DE, Walker BA, D’Annibale MA, McLaughlin K, Siddiq A, Kozikowski AP, Jaffrey SR, Twiss JL, Ratan RR, Langley B. HDAC6 is a target for protection and regeneration following injury in the nervous system. Proc Natl Acad Sci U S A. 106:19599-604, 2009.

Patent Status

Various U.S. patents filed and issued for Histone Deacetylase Inhibitors and Methods of Use and Isoform Selective HDAC Inhibitors