The inhibition of the β-TrCP-Nrf2 protein-protein interaction as a potential cancer therapeutic target

Abstract

The E3 ligase protein β-transducin repeats-containing proteins (β-TrCP) is an essential component of the ubiquitin proteasomal system (UPS), responsible for the maintenance of cellular protein levels within the body. Key target substrates for degradation include IκB, PDCD4 and FOXO3 alongside the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), responsible for cellular protection against oxidative damage. The tumour suppressive nature of the substrate targets and overexpression of β-TrCP seen within various cancers justifies its inhibition as a potential therapeutic for cancer. A small molecule substituted pyrazolone, GS143, alongside the natural product erioflorin have been identified as inhibitors of proteinprotein interactions (PPI) between β-TrCP and its targets as well as peptides based on sequences of the native ligands with KD values reported in the nanomolar range. This work centres on the design and synthesis of potential novel inhibitors of β-TrCP. Utilising in silico docking techniques through the modelling software AutoDock Vina and ICM-Pro, hit molecules have been selected for synthesis from various compound libraries. A selection of fragments, small molecules and peptides based on the binding sequences of native ligands were synthesised using a range of synthetic organic methods and purification procedures to produce a diverse library of compounds. The most promising compounds based on docking scores were screened in biophysical assays against the target protein. Molecular dynamics research was used to identify key residues involved in binding between prominent ligands and β-TrCP. Overall, this work has increased progress towards the discovery of a novel inhibitor of the E3 ligase β-TrCP