ArticleCommunications chemistry2025
Structure-based design of potent and selective inhibitors of the HECT ligase NEDD4.
Article in Communications chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
What it found
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The trial behind it
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Who cites it
5 citing papers in PubMed.
- HECT-type ubiquitin ligases: Emerging principles in the era of full-length structures.The Journal of biological chemistry · 2026Review
- Dual-targeted engineered mesenchymal stem cell-derived extracellular vesicles delivering Nedd4 attenuate renal fibrosis in diabetic kidney disease.Materials today. Bio · 2026Article
- Exploring Novel E3 Ligases and Neosubstrates for Molecular Glue Degraders and Therapeutic Applications in Cancer.Oncology research · 2026Review
- Selective ubiquitination of drug-like small molecules by the ubiquitin ligase HUWE1.Nature communications · 2025Article
- Covalent chemical probes.Communications chemistry · 2025Article
Corrections and comments
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Authors and funding
27 authors.
Funding
Abstract
Among the human E3 ubiquitin ligases, NEDD4 (Neural precursor cell expressed developmentally down-regulated 4) plays a critical role in development and cancer, making it a compelling therapeutic target. However, no specific NEDD4 inhibitors have advanced in drug development. In this study, we reveal the inhibitory mechanism of Norclomipramine, a tricyclic antidepressant, which inhibits NEDD4-mediated ubiquitin chain elongation by binding to a hydrophobic pocket in the Ub exosite of the N-lobe. Building on this mechanism, we conducted a focused medicinal chemistry campaign, resulting in the development of covalent inhibitors that specifically target the non-catalytic cysteine C627. These compounds exhibit selective binding to NEDD4 over other family members, effectively inhibiting NEDD4-mediated polyubiquitination while leaving monoubiquitinated substrates unaffected. Among these, compound 32 emerged as a potent lead (IC
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.