Design, synthesis and evaluation of inhibitors of POT1-DNA interactions

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Malik, Adnan Mahmood (2013) Design, synthesis and evaluation of inhibitors of POT1-DNA interactions. PhD thesis, University of Nottingham.

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Abstract

The unlimited replicative potential of cells is one of the hallmarks of cancer. Telomeres, DNA structures found at the ends of chromosomes have attracted a great deal of interest in recent years as potential anti-cancer drug targets since they play an important role in cancer cell immortality.

The repetitive TTAGGG sequences of telomeres are complexed to a group of six indispensible proteins, one of which is the protection of telomeres 1 (POT1) protein. This specialised protein binds to a ten nucleotide single stranded DNA sequence at the ends of chromosomes and plays an important role in telomere capping and length regulation. It has recently been proposed that the key function of POT1 is to suppress a potent DNA damage response at telomeres thereby protecting chromosome tips from being recognised as sites of DNA damage. Deletion of POT1 from telomeres in a variety of organisms including humans results in cytogenetic aberrations, senescence and cell death. These results indicate that POT1 is an integral telomere end-protection protein which is necessary for continued cellular proliferation and therefore POT1 is becoming a promising new target in cancer.

Using a structure-based approach, several small molecule inhibitors of POT1 have been designed to affect telomere integrity by disrupting the binding interaction of human POT1 with its target DNA sequence thereby driving cancer cells into senescence/apoptosis. Using a range of computational tools, a suitable drug binding pocket in POT1 has been identified and the de novo design of a specific class of POT1 inhibitor was completed. Using this novel scaffold, a small focussed library of hit-like compounds were synthesised and screened in a new POT1 fluorescence polarisation displacement assay developed by scientists at the University of Nottingham. In total, over 90 small molecule inhibitors based on two different scaffolds: pyrido[1,2-a]pyrimidines and sulfathiazoles have been synthesized with some inhibitors effectively decreasing POT1-DNA binding between 10-54% at 100μM ligand concentration. The biological results have established that electron-withdrawing substituents on the pendent phenyl ring of the pyrimidine core are essential for strong binding. These results have the potential to guide future development of improved lead compounds as therapeutics for the treatment of cancer.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Laughton, C.A.
Subjects: Q Science > QH Natural history. Biology > QH573 Cytology
Q Science > QP Physiology > QP501 Animal biochemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 31000
Depositing User: Hatton, Mrs Kirsty
Date Deposited: 07 Dec 2015 11:31
Last Modified: 19 Dec 2017 17:57
URI: https://eprints.nottingham.ac.uk/id/eprint/31000

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