ArticleThe Journal of biological chemistry2018
Derivatization of inhibitor of apoptosis protein (IAP) ligands yields improved inducers of estrogen receptor α degradation.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 103 citations in OpenAlex.
- Mechanisms and Design Principles of Proteolysis-Targeting Chimeras and Their Emerging Applications.ACS pharmacology & translational science · 2026Review
- Fulfilling multiple roles in PROTAC design: The emerging potential of oligonucleotides.European journal of medicinal chemistry · 2026Review
- Targeting the Undruggable: Recent Progress in PROTAC-Induced Transcription Factor Degradation.Cancers · 2025Review
- Targeted protein degraders of SARS-CoV-2 Mpro are more active than enzymatic inhibition alone with activity against nirmatrelvir resistant virus.Communications medicine · 2025Article
- Workflow for E3 Ligase Ligand Validation for PROTAC Development.ACS chemical biology · 2025Article
- Clozapine as an E3 Ligand for PROTAC Technology.ACS medicinal chemistry letters · 2025Article
- Research Progress of PROTAC-Degraded CDKs in the Treatment of Breast Cancer.Breast cancer (Dove Medical Press) · 2025Review
- Proteolysis Targeting Chimeras (PROTACs) in Breast Cancer Therapy.ChemMedChem · 2024Review
- PROTAC Beyond Cancer- Exploring the New Therapeutic Potential of Proteolysis Targeting Chimeras.Current topics in medicinal chemistry · 2024Review
- Development of DNA Aptamer-Based PROTACs That Degrade the Estrogen Receptor.ACS medicinal chemistry letters · 2023Article
- Heterobifunctional Ligase Recruiters Enable pan-Degradation of Inhibitor of Apoptosis Proteins.Journal of medicinal chemistry · 2023Article
- PROTAC'ing oncoproteins: targeted protein degradation for cancer therapy.Molecular cancer · 2023Review
- Current Status of Oligonucleotide-Based Protein Degraders.Pharmaceutics · 2023Review
- E3 ligase ligand optimization of Clinical PROTACs.Frontiers in chemistry · 2023Review
- Development of Gilteritinib-Based Chimeric Small Molecules that Potently Induce Degradation of FLT3-ITD Protein.ACS medicinal chemistry letters · 2022Article
- Proteolysis-targeting chimaeras (PROTACs) as pharmacological tools and therapeutic agents: advances and future challenges.Journal of enzyme inhibition and medicinal chemistry · 2022Review
- Recent advances in IAP-based PROTACs (SNIPERs) as potential therapeutic agents.Journal of enzyme inhibition and medicinal chemistry · 2022Review
- Estrogen Receptor-α Targeting: PROTACs, SNIPERs, Peptide-PROTACs, Antibody Conjugated PROTACs and SNIPERs.Pharmaceutics · 2022Review
- Discovery of E3 Ligase Ligands for Target Protein Degradation.Molecules (Basel, Switzerland) · 2022Review
- Recent Advances in PROTACs for Drug Targeted Protein Research.International journal of molecular sciences · 2022Review
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Authors and funding
18 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aberrant expression of proteins often underlies many diseases, including cancer. A recently developed approach in drug development is small molecule-mediated, selective degradation of dysregulated proteins. We have devised a protein-knockdown system that utilizes chimeric molecules termed specific and nongenetic IAP-dependent protein erasers (SNIPERs) to induce ubiquitylation and proteasomal degradation of various target proteins. SNIPER(ER)-87 consists of an inhibitor of apoptosis protein (IAP) ligand LCL161 derivative that is conjugated to the estrogen receptor α (ERα) ligand 4-hydroxytamoxifen by a PEG linker, and we have previously reported that this SNIPER efficiently degrades the ERα protein. Here, we report that derivatization of the IAP ligand module yields SNIPER(ER)s with superior protein-knockdown activity. These improved SNIPER(ER)s exhibited higher binding affinities to IAPs and induced more potent degradation of ERα than does SNIPER(ER)-87. Further, they induced simultaneous degradation of cellular inhibitor of apoptosis protein 1 (cIAP1) and delayed degradation of X-linked IAP (XIAP). Notably, these reengineered SNIPER(ER)s efficiently induced apoptosis in MCF-7 human breast cancer cells that require IAPs for continued cellular survival. We found that one of these molecules, SNIPER(ER)-110, inhibits the growth of MCF-7 tumor xenografts in mice more potently than the previously characterized SNIPER(ER)-87. Mechanistic analysis revealed that our novel SNIPER(ER)s preferentially recruit XIAP, rather than cIAP1, to degrade ERα. Our results suggest that derivatized IAP ligands could facilitate further development of SNIPERs with potent protein-knockdown and cytocidal activities against cancer cells requiring IAPs for survival.
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