Small molecule and peptide inhibitors of βTrCP and the βTrCP-NRF2 protein-protein interaction

The E3 ligase beta-transducin repeat-containing protein (beta TrCP) is an essential component of the ubiquitin-proteasome system that is responsible for the maintenance of cellular protein levels in human cells. Key target substrates for degradation include inhibitor of nuclear factor kappa B, programmed cell death protein 4 and forkhead box protein O3, alongside the transcription factor nuclear factor erythroid-2-related factor 2 (NRF2) that is responsible for cellular protection against oxidative damage. The tumour suppressive nature of many of its substrates and the overexpression of beta TrCP observed in various cancers support a potential therapeutic role for inhibitors in the treatment of cancer. A small molecule substituted pyrazolone, GS143, and the natural product erioflorin have been identified as inhibitors of beta TrCP and protect its targets from proteasomal degradation. Modified peptides based on the sequences of native substrates have also been reported with KD values in the nanomolar range. This review describes the current status of inhibitors of this E3 ligase. The scope for further inhibitor design and the development of PROTAC and molecular glue-type structures is explored in the context of beta TrCP as an example of WD40 domain-containing proteins that are gaining attention as drug targets.

Automated summary

The E3 ligase beta-transducin repeat-containing protein (beta TrCP) is a crucial component of the ubiquitin-proteasome system that maintains cellular protein levels in human cells. It targets various substrates for degradation, including factors involved in cellular protection against oxidative damage and tumor suppression. Inhibitors of beta TrCP, such as GS143 and erioflorin, have been identified, along with modified peptides. In this review, the current status of beta TrCP inhibitors is discussed, along with the potential for further inhibitor design and the development of new structures.