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

Dudey, Ashley P., Rigby, Jake M., Hughes, Gregory R., Stephenson, G. Richard ORCID: https://orcid.org/0000-0003-1487-9178, Storr, Thomas E., Chantry, Andrew and Hemmings, Andrew M. ORCID: https://orcid.org/0000-0003-3053-3134 (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:	07 Nov 2024 00:54
URI:	https://ueaeprints.uea.ac.uk/id/eprint/96472
DOI:	10.1080/14756366.2024.2394895

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