ArticleThe Journal of biological chemistry2011
Disruption of Bcr-Abl coiled coil oligomerization by design.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed.
- Dual inhibitors of CDK2 and TRKA kinases: design, synthesis, antiproliferative activity and molecular modeling of novel pyrazolopyrimidine derivatives.RSC advances · 2026Article
- Article
- Molecular Modeling of Single- and Double-Hydrocarbon-Stapled Coiled-Coil Inhibitors against Bcr-Abl: Toward a Treatment Strategy for CML.The journal of physical chemistry. B · 2024Article
- Molecular Mechanism of STIL Coiled-Coil Domain Oligomerization.International journal of molecular sciences · 2023Article
- Oncogenic driver FGFR3-TACC3 requires five coiled-coil heptads for activation and disulfide bond formation for stability.Oncotarget · 2023Article
- Higher-order interactions of Bcr-Abl can broaden chronic myeloid leukemia (CML) drug repertoire.Protein science : a publication of the Protein Society · 2023Article
- Kill Two Birds with One Stone: A Multifunctional Dual-Targeting Protein Drug to Overcome Imatinib Resistance in Philadelphia Chromosome-Positive Leukemia.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- Monomerization of ALK Fusion Proteins as a Therapeutic Strategy inFrontiers in oncology · 2020Article
- Review
- Evolution of AF6-RAS association and its implications in mixed-lineage leukemia.Nature communications · 2017Article
- A coiled-coil mimetic intercepts BCR-ABL1 dimerization in native and kinase-mutant chronic myeloid leukemia.Leukemia · 2015Article
- Re-engineered p53 chimera with enhanced homo-oligomerization that maintains tumor suppressor activity.Molecular pharmaceutics · 2014Article
- Cell-penetrating fusion peptides OD1 and OD2 interact with Bcr-Abl and influence the growth and apoptosis of K562 cells.Molecular and cellular biochemistry · 2014Article
- A chimeric p53 evades mutant p53 transdominant inhibition in cancer cells.Molecular pharmaceutics · 2013Article
- The DNA binding domain of p53 is sufficient to trigger a potent apoptotic response at the mitochondria.Molecular pharmaceutics · 2013Article
- Multidomain targeting of Bcr-Abl by disruption of oligomerization and tyrosine kinase inhibition: toward eradication of CML.Molecular pharmaceutics · 2013Article
- A single mutant, A276S of p53, turns the switch to apoptosis.Molecular pharmaceutics · 2013Article
- Disrupting BCR-ABL in combination with secondary leukemia-specific pathways in CML cells leads to enhanced apoptosis and decreased proliferation.Molecular pharmaceutics · 2013Article
- Article
- Enhanced and selective killing of chronic myelogenous leukemia cells with an engineered BCR-ABL binding protein and imatinib.Molecular pharmaceutics · 2012Article
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
Oligomerization is an important regulatory mechanism for many proteins, including oncoproteins and other pathogenic proteins. The oncoprotein Bcr-Abl relies on oligomerization via its coiled coil domain for its kinase activity, suggesting that a designed coiled coil domain with enhanced binding to Bcr-Abl and reduced self-oligomerization would be therapeutically useful. Key mutations in the coiled coil domain of Bcr-Abl were identified that reduce homo-oligomerization through intermolecular charge-charge repulsion yet increase interaction with the Bcr-Abl coiled coil through additional salt bridges, resulting in an enhanced ability to disrupt the oligomeric state of Bcr-Abl. The mutations were modeled computationally to optimize the design. Assays performed in vitro confirmed the validity and functionality of the optimal mutations, which were found to exhibit reduced homo-oligomerization and increased binding to the Bcr-Abl coiled coil domain. Introduction of the mutant coiled coil into K562 cells resulted in decreased phosphorylation of Bcr-Abl, reduced cell proliferation, and increased caspase-3/7 activity and DNA segmentation. Importantly, the mutant coiled coil domain was more efficacious than the wild type in all experiments performed. The improved inhibition of Bcr-Abl through oligomeric disruption resulting from this modified coiled coil domain represents a viable alternative to small molecule inhibitors for therapeutic intervention.
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Registered trials
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