ArticleNature structural & molecular biology2025
Design of PROTACs utilizing the E3 ligase GID4 for targeted protein degradation.
Article in Nature structural & molecular biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Targeted Lysosomal Degradation of Extracellular and Membrane Proteins: From Receptor Hijacking to Programmable Endolysosomal Routing.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- FBXO39 promotes LDHA-mediated aerobic glycolysis and colorectal cancer progression by p53 degradation.Journal of translational medicine · 2026Article
- Oncogenic SOX9-TRAIP signaling drives gastric cancer progression by mediating the degradation of the CPEB3-mTORC1 tumor suppressor axis.World journal of surgical oncology · 2026Article
- PROTAC-based protein degradation: a window of opportunity for melanoma therapy.Journal of biomedical science · 2026Review
- Recent advances in targeting protein degradation for tumor immunotherapy.Journal of hematology & oncology · 2025Review
- The many faces of the GID/CTLH E3 ligase complex.Biochemical Society transactions · 2025Review
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Authors and funding
18 authors.
Funding
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Abstract
Proteolysis targeting chimeras (PROTACs) hijack E3 ligases and the ubiquitin-proteasome system to achieve selective degradation of neo-substrates. Their ability to target otherwise intractable substrates has rendered them a valuable modality in drug discovery. However, only a handful of over 600 human E3 ligases have been functionalized for PROTAC applications. Here we show that the E3 ligase GID4 (glucose-induced degradation deficient complex 4) can be leveraged for targeted protein degradation using a noncovalent small molecule. We design and synthesize GID4-based PROTACs, exemplified by NEP162, which can eliminate endogenous BRD4 in a GID4- and ubiquitin-proteasome system-dependent manner. NEP162 exhibits antiproliferative activity and inhibits tumor growth in a xenograft model, hinting toward potential anticancer applications. We further present the crystal structures of GID4-PROTAC-BRD4 ternary complexes in three distinct states, unveiling plastic interactions between GID4 and BRD4. These structural insights, combined with in vitro and in vivo data, decipher the molecular basis by which the hereby developed PROTACs recruit BRD4 to GID4 for targeted degradation and expand our arsenal of PROTAC-exploitable E3 ligases.
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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.