Currently available projects

« Back

Isoform-selective Histone Deacetylase Inhibitors

Information

  • Start date: October 2013
  • Programme: PhD
  • Mode of Study: Full Time
  • Studentship Length: 3 years

How to Apply

  • Deadline: 31 July 2013. Applications are processed as soon as they are received, so early application is encouraged. NB applicants who wish to start their studies in October 2013 should submit their application by 31 July 2013 at the very latest. Applications received after this date will be considered for the January 2014 entry point if the project is still available.
  • Apply online

Fees & Funding

Entry Requirements

  • Acceptable First Degree:

    Chemistry, Pharmacy

  • Minimum Entry Standard: The standard minimum entry requirement is 2:1.

Project Description

A key epigenetic modification in histones and other proteins is the acetylation of lysine residues. This process is reversible as acetyllysine residues are hydrolysed back to lysine, a reaction catalysed by histone deacetylases (HDACs). There are 18 HDACs in the human genome, and their upregulation is implicated in a number of diseases including cancer, inflammation and neurodegenerative disorders. For these reasons, the development of HDAC inhibitors is an important approach to drug discovery and two are already clinically approved for the treatment of cancer.

In this project we will synthesise a series of second generation HDAC inhibitors with high potency as well as selectivity for individual HDACs. Such compounds will potentially overcome the side effects observed with nonselective HDAC inhibitors and potentially useful leads for new therapeutic agents.

The project will be an interdisciplinary mix of organic synthesis and molecular biology. The project will be a continuation of our extensive work on HDAC inhibitors starting from natural products.

References

(i) Davies, E. R.; Haitchi, H. M.; Thatcher, T. H.; Sime, P. J.; Kottmann, R. M.; Ganesan, A.; Packham, G.; O'Reilly, K. M. A. Davies, D. E. Spiruchostatin A Inhibits Proliferation and Differentiation of Fibroblasts from Patients with Pulmonary Fibrosis. Am. J. Resp. Cell Mol. Biol. 2012, 46, 687-694.
(ii) Benelkebir, H.; Donlevy, A. M.; Packham, G.; Ganesan, A. Total Synthesis and Stereochemical Assignment of Burkholdac B, a Depsipeptide HDAC Inhibitor. Org. Lett. 2011, 13, 6334-6337.
(iii) Benelkebir, H.; Marie, S.; Hayden, A.; Lyle, J.; Loadman, P.; Crabb, S. J.; Packham, G.; Ganesan, A. Total Synthesis of Largazole and Analogues: HDAC Inhibition, Antiproliferative Activity and Metabolic Stability. Bioorg. Med. Chem. 2011, 19, 3650-3658.
(iv) Yurek-George, A.; Cecil, A.; Mo, A. H. K.; Wen, S.; Rogers, H.; Habens, F.; Maeda, S.; Yoshida, M.; Packham, G.; Ganesan, A. The First Biologically Active Synthetic Analogues of FK228, the Depsipeptide Histone Deacetylase Inhibitor. J. Med. Chem. 2007,50, 5720-5726.



Apply online