3,3′-Diindolylmethane (DIM): A molecular scaffold for inhibition of WWP1 and WWP2, members of the NEDD4 family HECT E3 ligases

Dudey, Ashley P., Hughes, Gregory R., Rigby, Jake M., Monaco, Serena, Stephenson, G. Richard, Storr, Thomas E., Angulo, Jesus, Chantry, Andrew and Hemmings, Andrew M. (2025) 3,3′-Diindolylmethane (DIM): A molecular scaffold for inhibition of WWP1 and WWP2, members of the NEDD4 family HECT E3 ligases. ACS Omega, 10 (6). 5963–5972. ISSN 2470-1343

Preview

PDF (Dudey_et-al_2025_ACSOmega) - Published Version Available under License Creative Commons Attribution. Download (4MB) | Preview

Abstract

Indole-3-carbinol (I3C) is a metabolic derivative of glucobrassicin found in cruciferous vegetables. Known for its anticarcinogenic properties, I3C has been shown to target the NEDD4 family HECT E3 ligases, NEDD4-1 and WWP1, yet in vitro confirmation for the latter is lacking. Here, we characterize the interactions of I3C and a set of 17 derivatives with WWP1 and its homologue, WWP2. Saturation transfer difference (STD) NMR analysis confirmed strong interaction of I3C with WWP1 but weaker with WWP2. However, while autoubiquitination activity assays revealed weak inhibition of WWP1, the I3C condensation product, 3,3′-diindolylmethane (DIM), was more potent (IC50 111.2 μM; 95% CI = 85.1, 145.8). Molecular modeling of DIM to the ubiquitin exosite of both enzymes suggested the WW2 domain makes hydrophobic interactions with the ligand that may contribute to inhibitory action. Taken together, our results suggest future drug lead development should focus on the SAR between WWP1 and DIM.

Item Type:	Article
Additional Information:	Funding information: The work was supported by funding to G.R.H. and A.C. from the Big C Cancer Charity (Research Grant 19-14R) supporting a PhD studentship for JMR. A.P.D. was supported by a University of East Anglia (UEA) Science Faculty PhD Studentship.
Uncontrolled Keywords:	chemistry(all),chemical engineering(all) ,/dk/atira/pure/subjectarea/asjc/1600
Faculty \ School:	Faculty of Science > School of Biological Sciences Faculty of Science > School of Chemistry, Pharmacy and Pharmacology Faculty of Science > School of Chemistry (former - to 2024)
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	24 Feb 2025 10:30
Last Modified:	02 Mar 2025 06:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/98567
DOI:	10.1021/acsomega.4c09944

Downloads

Actions (login required)

View Item