Design and synthesis of novel classes of HDACs and KMTs inhibitors

Narozny, Remy (2018) Design and synthesis of novel classes of HDACs and KMTs inhibitors. Doctoral thesis, University of East Anglia.

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For long, scientists thought that our body was driven only by our genetic code that we inherited at birth. However, this determinism was shattered entirely and proven as false in the second half of the 21st century with the discovery of epigenetics. Instead, cells turn genes on and off using reversible chemical marks. With the tremendous progression of epigenetic science, it is now believed that we have a certain power over the expression of our genetic traits. Over the years, these epigenetic modifications were found to be at the core of how diseases alter healthy cells, and environmental factors and lifestyle were identified as top influencers. Epigenetic dysregulation has been observed in every major domain of medicine, with a reported implication in cancer development, neurodegenerative pathologies, diabetes, infectious disease and even obesity. Substantially, an epigenetic component is expected to be involved in every human disease. Hence, the modulation of these epigenetics mechanisms has emerged as a therapeutic strategy. Histone deacetylases (HDAC) are silencing epigenetic markers involved in the mediation of the acetylation system. Aberrant HDAC activities have been associated with the development of a broad range of pathologies, and HDAC inhibition is highly regarded as a potential therapeutic target. This approach became successful with the approval by the FDA of several epidrugs. However, they present undesired side effects. Lack of selectivity was identified as a principal suspect and, therefore, the development of novel compounds that would target more selectively the epigenetics enzymes represent a major axis of research for future pharmacological applications.

Accordingly, this work focus on designing new classes of HDAC inhibitors. A variety of structures, build around the use of amino acids, were explored and potential inhibitors were produced with different cores. These series were then evaluated in enzymatic inhibition assays on HDAC and in cell growth inhibition assays on leukaemia cell lines. Additionally, we were also involved in the international consortium A-ParaDDisE that aimed to develop epigenetic modulators as drug candidates against the main parasitic diseases: malaria, schistosomiasis, leishmaniasis and Chagas disease. This collaboration resulted in the identification of critical targets for the different parasites and the development of testing methods to move compounds toward clinical development. The antischistosomal effect of some of our inhibitors was, thus, evaluated. Finally, a side project was carried at the University of Salerno in Italy in a short-term scientific mission that aimed to develop a new class of SETD8 methyltransferase inhibitors.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Users 9280 not found.
Date Deposited: 13 Jun 2019 12:40
Last Modified: 13 Jun 2019 12:40

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