The work described within this thesis relates to the development and identification of
novel inhibitors of two recently identified chemotherapeutic targets.i/ii
Apurinic/Apyrimidinic Endonuclease 1 – (Ape1/Ref1)i
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.
Liver Receptor Homolog-1 (LRH-1)ii
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.