Studies toward evaluating Gcn2 as a drug target : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Genetics at Massey University, Albany, New Zealand. EMBARGOED until 24 March 2027.
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Date
2020
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Massey University
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Abstract
All living organisms are subject to dynamic environmental conditions. In order to survive a changing environment, organisms have evolved the capacity to adapt to stressors; this adaptation response occurs on both physiological and cellular levels. The majority of organisms face periods of inconsistent nutrient supply, which require cells to regulate consumption and conservation of vital resources such as amino acids and glucose. Amino acids are a fundamental nutrient essential for macromolecule biosynthesis; they are the monomeric unit of proteins, required for practically every cellular function. The amino acid stress response pathway regulates amino acid conservation when intracellular amino acid depletion occurs under physiological and pathological conditions; a key constituent of this pathway is Gcn2.
Gcn2 is a ubiquitous eukaryotic protein kinase. Gcn2 is necessary for the maintenance of cellular homeostasis in response to amino acid deprivation and other physiological stressors such as UV irradiation and glucose, purine, or carbohydrate deprivation; Gcn2 not only aids survival in response to these regular physiological events but, on the other hand, is crucial for the progression of some pathologies, which include cancer. Gcn2 activity contributes to the growth and maintenance of tumours; it is, therefore, recognised as a prospective anti-cancer drug target. Inhibition of Gcn2 may be an effective strategy for impeding cancer cell proliferation and tumour growth as a stand-alone therapy or as a component of a combined therapeutic approach.
In this study, we combined computational and experimental analytical methods to identify Gcn2 inhibitors and examined the effects of Gcn2 inhibition on cancer cells in combination with currently used cancer therapies.--Shortened abstract
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Embargoed until 24 March 2027
Keywords
Protein kinases, Inhibitors, Therapeutic use, Antineoplastic agents