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The development of Nrf2 inducing compounds ascytoprotective agents

11 December 2014

Project description

  • The aims of this project are to develop a new series of compounds with cytoprotective and chemopreventive activity.
  • The transcription factor Nrf2 orchestrates the expression a range of cytoprotective genes in cells. Up-regulating Nrf2 activity has broad anti-inflammatory and cytoprotective activity that has potential preventive and disease modifying activity in neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases and cancer.
  • A key drug target is Keap1, the principle negative regulator of Nrf2. Inhibiting the direct protein-protein interaction between Keap1 and Nrf2 in order to block the ubiquitination and destruction of Nrf2 is the drug design objective of this project.
  • We have used in silico drug design techniques to identify small molecules and peptides that may bind to the Keap1 Nrf2 binding pocket. A large series of potential inhibitors were synthesised and screened using a fluorescence polarisation assay that we developed and validated in-house. Addition

    nrf2-figure1

    ally, we have screened the compounds in cell-based assays for their ability to increase the expression of Nrf2-dependent target genes.

  • With our collaborators, we have identified both small molecules and peptides that inhibit the protein-protein interaction and up-regulate Nrf2 target genes including NAD(P)H quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO1) and p62/sequestosome-1. In particular, one of the lead structures, HB229, has intriguing activity as an inducer of mitochondrial quality control processes in cells (mitophagy), a process that is mediated by p62.
  • The compounds are promising leads for further development as chemical probes and as drug candidates for therapeutic applications.

People involved

Principal Investigator: Geoff Wells

Collaborators: John Hayes and Albena Dinkova-Kostova (University of Dundee), Michelangelo Campanella (Royal Veterinary College), Eng Hui Chew (National University of Singapore), Shozeb Haider (UCL School of Pharmacy)

Funding

Cancer Research UK; BBSRC (as Co-I)

Publications

Schaap, M; Hancock, R.; Wilderspin, A.; Wells, G. Development of a steady-state FRET-based assay to identify inhibitors of the Keap1-Nrf2 protein-protein interaction. Prot. Sci. 2013, 22, 1812-1819.

Hancock, R.; Schaap, M.; Pfister, H.; Wells, G. Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction with improved binding and cellular activity. Org Biomol Chem, 2013, 11, 3553-3557.

Schaap, M; Hancock, R.; Wilderspin, A.; Wells, G. Development of a steady-state FRET-based assay to identify inhibitors of the Keap1-Nrf2 protein-protein interaction. Prot. Sci. 2013, 22, 1812-1819. Hancock, R.; Schaap, M.; Pfister, H.; Wells, G. Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction with improved binding and cellular activity. Org Biomol Chem, 2013, 11, 3553-3557. Hancock, R.; Bertrand, H. C.; Tsujita, T.; Naz, S.; El-Bakry, A.; Laoruchupong, J.; Hayes, J.D.; Wells, G. Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction. Free Radic. Biol. Med. 2012, 52, 444-451.

Further information

Dr. Geoff Wells

http://www.ucl.ac.uk/pharmacy/people/academic-research-staff-profiles/ge...

Contact: g.wells@ucl.ac.uk