Erasing the eraser. The synthesis and biological evaluation of some novel epigenetic inhibitors.

Lee, Adam (2020) Erasing the eraser. The synthesis and biological evaluation of some novel epigenetic inhibitors. Doctoral thesis, University of East Anglia.

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Abstract

Epigenetic abnormalities have been implicated in a wide variety of disorders and as such are of increasing interest as potential drug targets. Histone deacetylases (HDACs) and Lysine Specific Demethylase 1 (LSD1) are two such targets that have received significant attention in recent times. Although both enzymes have been found to be crucial in several regulatory roles, their overexpression has been observed in a number of cancers. Several HDAC inhibitors are already approved for use in various cancers and a number of LSD1 inhibitors are currently in clinical trials.

The lack of approved inhibitors for LSD1 and the lack of isoform specific inhibitors of the HDACs suggests a need for further research and development in both of these key areas of epigenetic drug discovery. In addition, the ability of cancer as a disease to become resistant to treatment is a major hurdle.

Evidence is now emerging that combining both HDAC and LSD1 inhibitors can have a synergistic effect in cancer. To that end, we have developed a dual LSD1/HDAC inhibitor based upon the structure of GSK2879552, the clinical candidate of GlaxoSmithKline. This dual inhibitor aims to take advantage of any synergistic effect between LSD1 and HDAC, as well as addressing the problem of drug resistance through the mode of dual target engagement.

Further, we have developed a novel, potent, LSD1 inhibitor with good in cell activity. This was followed up with the synthesis of several analogues with the aim of working towards further structure optimisation.

Work on our dual inhibitor, led to the development of two novel HDAC6 inhibitors with promising activity both in and out of cell. Again, the series was extended in order to determine if this activity could be further improved.

Finally, a novel HDAC inhibitor comprising a carboxylic acid zinc binding motif, and low µM levels of activity is presented.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Pharmacy
Depositing User:	Chris White
Date Deposited:	15 Apr 2021 13:19
Last Modified:	15 Apr 2021 13:19
URI:	https://ueaeprints.uea.ac.uk/id/eprint/79785
DOI:

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