ArticleNature chemistry2024
Proteolysis-targeting chimeras with reduced off-targets.
Article in Nature chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
What it found
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Who cites it
63 citing papers in PubMed, 109 citations in OpenAlex.
- Evolving CRBN ligands enhance the drug-like properties of protein degraders.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Advancing PROTAC therapeutics through chemistry-guided design of smart delivery systems.Acta pharmacologica Sinica · 2026Review
- A Versatile DNA-Encoded Library Platform for the Discovery of Highly Cooperative Chemical Inducers of Proximity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Targeted degradation of hepatic KEAP1 mitigates drug-induced liver injury via dual boosting NRF2 and PGAM5 signaling.Redox biology · 2026Article
- High-throughput ligand diversification to discover chemical inducers of proximity.Nature chemical biology · 2026Article
- Cyclins and Cyclin-Dependent Kinases: Structure, Biological Functions, and Innovative Targeting Strategies in Cancer.MedComm · 2026Review
- The synthetic landscape of cereblon (CRBN) binders: from thalidomide to emerging chemotypes.Chemical Society reviews · 2026Review
- TogoPhosTAC as a delivery-ready platform for targeted protein dephosphorylation.Nature communications · 2026Article
- Programmable nanomedicine via bioorthogonal molecular engineering.Nano convergence · 2026Review
- Article
- Targeted Protein Degradation of NUDT5 Dissociates Catalytic Inhibition from Protein Loss in 6-Thioguanine Response.Nature communications · 2026Article
- ALK rearrangements and resistance mutations in non-small cell lung cancer: molecular mechanisms and therapeutic implications.Cancer chemotherapy and pharmacology · 2026Review
- An orally active dual CBP/p300 degrader targets core dependencies of multiple myeloma.Cell reports · 2026Article
- STAT Signaling in Metabolic Disorders: From Molecular Mechanisms to Therapeutic Implications.Cell biochemistry and biophysics · 2026Review
- Development of PROTACs for targeted degradation of oncogenic TRK fusions.RSC chemical biology · 2026Article
- A dihydrouracil CRBN ligand mitigates IMiD associated safety liabilities in heterobifunctional targeted protein degrader.Nature communications · 2026Article
- PROTAC-Mediated Targeted Degradation of MDM2 Induces Tumor-Suppressive Signaling in Osteosarcoma Cells.Cells · 2026Article
- Proof of concept: targeted protein degradation of the stress granules component G3BP1 as an antiviral strategy against norovirus infection.Antimicrobial agents and chemotherapy · 2026Article
- Zinc finger proteins (ZFPs) in health and disease.Molecular biomedicine · 2026Review
- Class IIa HDACs forced degradation allows resensitization of oxaliplatin-resistant FBXW7-mutated colorectal cancer.Molecular oncology · 2026Article
3 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
Abstract
Proteolysis-targeting chimeras (PROTACs) are molecules that induce proximity between target proteins and E3 ligases triggering target protein degradation. Pomalidomide, a widely used E3 ligase recruiter in PROTACs, can independently degrade other proteins, including zinc-finger (ZF) proteins, with vital roles in health and disease. This off-target degradation hampers the therapeutic applicability of pomalidomide-based PROTACs, requiring development of PROTAC design rules that minimize off-target degradation. Here we developed a high-throughput platform that interrogates off-target degradation and found that reported pomalidomide-based PROTACs induce degradation of several ZF proteins. We generated a library of pomalidomide analogues to understand how functionalizing different positions of the phthalimide ring, hydrogen bonding, and steric and hydrophobic effects impact ZF protein degradation. Modifications of appropriate size on the C5 position reduced off-target ZF degradation, which we validated through target engagement and proteomics studies. By applying these design principles, we developed anaplastic lymphoma kinase oncoprotein-targeting PROTACs with enhanced potency and minimal off-target 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.