Recently the development of small molecule bromodomain ligands has been the focus of significant attention from the medicinal chemistry community. The bromodomain and extra C-terminal domain (BET) family of bromodomain-containing proteins (BCPs) have emerged as important therapeutic targets for cancer and inflammation therapy, and focus has now turned to developing ligands for non-BET BCPs, to determine their function and therapeutic potential.
Bromodomains are epigenetic reader proteins that bind to acetylated lysine (KAc) residues, these fundamental interactions play a key role in regulation of important transcriptional protein-protein interactions that regulate the expression of certain genes.
Here we report the design, synthesis, and biological evaluation of a range of potent and selective ligands for the CREBBP bromodomain, which is a key transcriptional co-activator.
Objective 1. Our initial hit molecule contained a metabolically unstable dihydroquinoxalinone acetyl-lysine mimicking 'head group' and an aryl amide. The acetyl-lysine mimicking 'head group' was developed into a more metabolically stable benzodiazepinone it's ring expanded head group containing an additional CH2 reduces degradation, as oxidation of dihydroquinoxalinone gives an aromatised quinoxalinone with reduced activity.
Objective 2. Although improving metabolic stability introduction of the benzodiazepinone caused the molecules internal hydrogen bonding network to change, a reduced affinity binding conformation now formed in solution. The internal hydrogen bonding in the presence of the benzodiazepinone head group was a hinderance. Thus we re removed the aryl amide and replaced it with an E-alkene a classical amide bio-isostere.
