ArticleCancer science2017
Development of protein degradation inducers of oncogenic BCR-ABL protein by conjugation of ABL kinase inhibitors and IAP ligands.
Article in Cancer science, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 98 citations in OpenAlex.
- Targeted degradation of protein in hematologic malignancies: mechanisms, therapeutic strategies, and clinical prospects.Cancer gene therapy · 2026Review
- Article
- Advances in targeted therapies for pediatric tumors.Acta pharmacologica Sinica · 2026Article
- Induced proximity-based therapeutic modalities.Nature reviews. Drug discovery · 2026Review
- FDA-approved kinase inhibitors in PROTAC design, development and synthesis.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Research Progress of PROTAC-Degraded CDKs in the Treatment of Breast Cancer.Breast cancer (Dove Medical Press) · 2025Review
- Discovery of Potent Degraders of the Dengue Virus Envelope Protein.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Exploiting the potential of the ubiquitin-proteasome system in overcoming tyrosine kinase inhibitor resistance in chronic myeloid leukemia.Genes & diseases · 2024Review
- BCR::ABL1 Proteolysis-targeting chimeras (PROTACs): The new frontier in the treatment of PhLeukemia · 2024Review
- Reversible control of kinase signaling through chemical-induced dephosphorylation.Communications biology · 2024Article
- Discovery of Potent Degraders of the Dengue Virus Envelope Protein.bioRxiv : the preprint server for biology · 2024Article
- PROteolysis-Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives.MedComm · 2024Review
- The Progress of Small Molecule Targeting BCR-ABL in the Treatment of Chronic Myeloid Leukemia.Mini reviews in medicinal chemistry · 2024Review
- Review
- Isolation and characterization of β-transducin repeat-containing protein ligands screened using a high-throughput screening system.Oncology research · 2023Article
- Targeting the PTP1B-Bcr-Abl1 interaction for the degradation of T315I mutant Bcr-Abl1 in chronic myeloid leukemia.Cancer science · 2023Article
- Recent advancements in targeted protein knockdown technologies-emerging paradigms for targeted therapy.Exploration of targeted anti-tumor therapy · 2023Review
- 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
- Targeting micro-environmental pathways by PROTACs as a therapeutic strategy.Seminars in cancer biology · 2022Review
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chromosomal translocation occurs in some cancer cells, which results in the expression of aberrant oncogenic fusion proteins that include BCR-ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase, such as imatinib and dasatinib, exhibit remarkable therapeutic effects, although emergence of drug resistance hampers the therapy during long-term treatment. An alternative approach to treat CML is to downregulate the BCR-ABL protein. We have devised a protein knockdown system by hybrid molecules named Specific and Non-genetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers (SNIPER), which is designed to induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins, and a couple of SNIPER(ABL) against BCR-ABL protein have been developed recently. In this study, we tested various combinations of ABL inhibitors and IAP ligands, and the linker was optimized for protein knockdown activity of SNIPER(ABL). The resulting SNIPER(ABL)-39, in which dasatinib is conjugated to an IAP ligand LCL161 derivative by polyethylene glycol (PEG) × 3 linker, shows a potent activity to degrade the BCR-ABL protein. Mechanistic analysis suggested that both cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP) play a role in the degradation of BCR-ABL protein. Consistent with the degradation of BCR-ABL protein, the SNIPER(ABL)-39 inhibited the phosphorylation of signal transducer and activator of transcription 5 (STAT5) and Crk like proto-oncogene (CrkL), and suppressed the growth of BCR-ABL-positive CML cells. These results suggest that SNIPER(ABL)-39 could be a candidate for a degradation-based novel anti-cancer drug against BCR-ABL-positive CML.
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