Jaffry, Uzma;
Wells, Geoff;
(2023)
Small molecule and peptide inhibitors of βTrCP and the βTrCP–NRF2 protein–protein interaction.
Biochemical Society Transactions
, 51
(3)
, Article BST20220352. 10.1042/BST20220352.
(In press).
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Abstract
The E3 ligase beta-transducin repeat-containing protein (βTrCP) 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 βTrCP 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 βTrCP 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 βTrCP as an example of WD40 domain-containing proteins that are gaining attention as drug targets.
Type: | Article |
---|---|
Title: | Small molecule and peptide inhibitors of βTrCP and the βTrCP–NRF2 protein–protein interaction |
Location: | England |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1042/BST20220352 |
Publisher version: | https://doi.org/10.1042/BST20220352 |
Language: | English |
Additional information: | © The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY). Open access for this article was enabled by the participation of University College London in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society under a transformative agreement with JISC. |
Keywords: | βTrCP, cancer, drug discovery and design, NRF2 |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
URI: | https://discovery.ucl.ac.uk/id/eprint/10172105 |
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