The synthesis and biological characterisation of high affinity, selective macrocyclic ligands targeting the CREBBP/p300 bromodomains

Thesis

Lysine acetylation of histone tails is a post-translational modification recognised by epigenetic “reader” domains, otherwise known as bromodomains. These proteins aid in regulating cellular processes and have been implicated in multiple diseases, particularly in cancer. A pair of bromodomain-containing proteins of particular interest are the paralogues CBP and p300. These large multi-domain proteins play a key role in gene expression through their recruitment of transcription factors onto DNA, both of these paralogues contain bromodomains. Recently they have emerged as a promising oncology target with efforts conducted to produce inhibitors of the bromodomain, thus preventing oncogene expression and cancer cell proliferation. The challenge of developing bromodomain inhibitors is that target selectivity often proves difficult. In order to overcome this selectivity problem, building upon previous work within the Conway group macrocyclic ligands were synthesised to gain selectivity, unfortunately these original macrolactams demonstrated significantly weaker affinity for the CREBBP bromodomain (CBPBRD). The work presented herein attempts to overcome this decrease in affinity through SAR investigation, identifying compound 19 as a high-affinity and highly selective macrocyclic ligand for the CBPBRD.

Authors: Boyd, AM

• DOI: 10.5287/ora-9ozwn5jxp
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: synthesis; organic chemistry; drug discovery; macrocycles; biophysic; medicinal chemistry; bromodomains; structure based design
• Subjects: Pharmaceutical chemistry; Chemistry, Organic