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Title: Synthetic studies towards novel inhibitors of Ape1/Ref1 and LRH-1
Author: Brookes, Paul Andrew
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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The work described within this thesis relates to the development and identification of novel inhibitors of two recently identified chemotherapeutic targets: (i) Apurinic/Apyrimidinic Endonuclease 1-(Ape1/Ref1). The base excision repair (BER) pathway is a vital eukaryotic process that acts to recognise, process and remove damaged DNA from the genome. A critical step in BER involves the processing of an apurinic/apyrimidinic (AP) site intermediate by Ape1/Ref1. Such AP site intermediates are generated when DNA bases undergo spontaneous damage, and as such are continuously and ubiquitously being generated. Therefore, through its innate function Ape1/Ref1 offers direct protection to cells from the effects of DNA damaging agents, including commonly employed chemotherapeutics. Interestingly, Ape1/Ref1 is over-expressed in many cancers and this particularity has been shown to correlate with resistances to both radio and chemotherapy regimens. Considering this, Ape1/Ref1 has emerged as a potential chemotherapeutic target. The availability of robust X-ray crystal data allowed for the implementation of a grass roots computer-aided drug design (CADD) approach. Multiple inhibitor scaffolds were identified, designed, synthesised and biologically evaluated in vitro. Furthermore, during this project several publications emerged detailing novel inhibitors of Ape1/Ref1, investigations into these reports are detailed within. (ii) Liver Receptor Homolog-1 (LRH-1). Nuclear receptors (NRs) are ligand regulated transcription factors and have been described as nearly ideal drug targets due to their three-dimensional structure. NRs contain vast hydrophobic internal pockets that bind to hydrophobic, drug-like molecules. In the presence of a natural endogenous substrate, ligand-induced conformational changes modulate the recruitment of transcriptional regulators to gene promoters. Liver receptor homolog-1 is a NR that has recently been shown to modulate the estrogen response in breast cancers through the regulation of estrogen receptor-α (ERα) expression. Resorcylic acid lactones (RALs) were recently shown by Barrett et. al. to be capable of antagonising this receptor in the low micromolar range. Such action could possibly translate to the potential blocking of co-activator recruitment and ERα expression in vivo and therefore these compounds served as a start point for a ligand based drug discovery campaign. Additional synthetic investigations and biological developments upon these RALs are discussed and detailed within.
Supervisor: Barrett, Anthony Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral