Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases

Dudey, Ashley P., Rigby, Jake M., Hughes, Gregory R., Stephenson, G. Richard, Storr, Thomas E., Chantry, Andrew and Hemmings, Andrew M. (2024) Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases. Journal of Enzyme Inhibition and Medicinal Chemistry, 39 (1). ISSN 1475-6366

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Abstract

The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC50 of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC50 of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.

Item Type:	Article
Additional Information:	Data availability statement: The crystal structures of WWP1 and WWP2 are openly available in the RCSB Protein Data Bank with accession codes 9EQK (https://doi.org/10.2210/pdb9EQK/pdb) and 9EQH (https://doi.org/10.2210/pdb9EQH/pdb), respectively. The authors confirm that further data supporting the findings of this study are available within the article and its supplementary materials. Funding information: The work was supported by funding to G.R.H. and A.C. from BigC Cancer Charity (Research Grant 19-14R) supporting a PhD studentship for J.M.R. A.P.D. was supported by a University of East Anglia (UEA) Science Faculty PhD Studentship.
Uncontrolled Keywords:	ubiquitin ligase inhibitors,drug discovery,sar,wwp1,wwp2,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Science Faculty of Science > School of Biological Sciences Faculty of Science > School of Chemistry (former - to 2024) Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
UEA Research Groups:	Faculty of Science > Research Groups > Chemistry of Materials and Catalysis Faculty of Science > Research Groups > Plant Sciences Faculty of Science > Research Groups > Molecular Microbiology Faculty of Science > Research Groups > Chemistry of Life Processes Faculty of Science > Research Centres > Centre for Molecular and Structural Biochemistry
Depositing User:	LivePure Connector
Date Deposited:	03 Sep 2024 14:33
Last Modified:	06 Feb 2025 12:12
URI:	https://ueaeprints.uea.ac.uk/id/eprint/96472
DOI:	10.1080/14756366.2024.2394895

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