ArticleJournal of the American Chemical Society2021
Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation.
Article in Journal of the American Chemical Society, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed.
- Targeted proteoform degradation for precision drug design, delivery, and therapy.Drug delivery · 2026Review
- A pharmacological modality to sequester homomeric proteins.Nature chemical biology · 2026Article
- Aryl Aldehyde-Anchored Small Molecules Recruit FBXO22 for Targeted Degradation of NSD2.Journal of medicinal chemistry · 2026Article
- Discovery of a KLHL41 Ligand for Muscle Specific Protein Degradation.Nature communications · 2026Article
- Proteolysis-targeting chimera (PROTAC) in cancer: design principles and applications on "undruggable" targets.Biomarker research · 2026Review
- Keap1-Kelch-targeting protein-protein interaction inhibitors, but not reversibly-binding electrophiles, increase the thermostability of Keap1 in the cellular environment.RSC chemical biology · 2026Article
- The application of drug delivery systems based on targeted protein degradation chimeras in disease treatment strategies.Journal of nanobiotechnology · 2026Review
- Identification of KLHL12 Ligands Using Fragment-Based Methods.Journal of medicinal chemistry · 2026Article
- Discovery of SKP2-Recruiting PROTACs for Target Protein Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Induced proximity-based therapeutic modalities.Nature reviews. Drug discovery · 2026Review
- Targeted Protein Degradation in Cancer: PROTACs, New Targets, and Clinical Mechanisms.Biomolecules · 2026Review
- Fadraciclib, a CDK2/CDK9 inhibitor, shows efficacy in biliary tract cancer and synergistic potential with olaparib and JQ1 based on MCL1 expression.Cell communication and signaling : CCS · 2025Article
- Context Matters: E3 Ligase-Ligand Pairing Strategies for Optimized PROTAC Performance.Protein & cell · 2025Article
- Recent advances in targeting protein degradation for tumor immunotherapy.Journal of hematology & oncology · 2025Review
- Engineered platelets as targeted protein degraders and application to breast cancer models.Nature biotechnology · 2025Article
- Article
- Reduced Pressure Ionization Enhances Native Mass Spectrometry of Proteins and Protein Complexes.Angewandte Chemie (International ed. in English) · 2025Article
- Deubiquitinase-Targeting Chimeras Mediated Stabilization of Tumor Suppressive E3 Ligase Proteins as a Strategy for Cancer Therapy.Journal of the American Chemical Society · 2025Article
- Chemical knockdown of Keap1 and homoPROTAC-ing allergic rhinitis.Acta pharmaceutica Sinica. B · 2025Article
- Advancing Design Strategy of PROTACs for Cancer Therapy.MedComm · 2025Review
2 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
16 authors.
Funding
Abstract
Proteolysis targeting chimeras (PROTACs) represent a new class of promising therapeutic modalities. PROTACs hijack E3 ligases and the ubiquitin-proteasome system (UPS), leading to selective degradation of the target proteins. However, only a very limited number of E3 ligases have been leveraged to generate effective PROTACs. Herein, we report that the KEAP1 E3 ligase can be harnessed for targeted protein degradation utilizing a highly selective, noncovalent small-molecule KEAP1 binder. We generated a proof-of-concept PROTAC, MS83, by linking the KEAP1 ligand to a BRD4/3/2 binder. MS83 effectively reduces protein levels of BRD4 and BRD3, but not BRD2, in cells in a concentration-, time-, KEAP1- and UPS-dependent manner. Interestingly, MS83 degrades BRD4/3 more durably than the CRBN-recruiting PROTAC dBET1 in MDA-MB-468 cells and selectively degrades BRD4 short isoform over long isoform in MDA-MB-231 cells. It also displays improved antiproliferative activity than dBET1. Overall, our study expands the limited toolbox for targeted protein degradation.
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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.