دورية أكاديمية
AcGlcAs: A Novel P53-Targeting Arsenical with Potent Cellular Uptake and Cancer Cell Selectivity
| العنوان: | AcGlcAs: A Novel P53-Targeting Arsenical with Potent Cellular Uptake and Cancer Cell Selectivity |
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| المؤلفون: | Ying Liang, Quanlin An, Huaxin Song, Yigang Tang, Shujun Xiao, Jiale Wu, Ni Yan, Biao Yu, Xin Cao, Min Lu |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Biophysics, Biochemistry, Cell Biology, Genetics, Molecular Biology, Pharmacology, Biotechnology, Cancer, Chemical Sciences not elsewhere classified, similar binding mechanism, potential clinical candidate, potent cellular uptake, poor cellular uptake, frequently mutated protein, acglcas significantly extended, targeting ato trials, targeting arsenical, xenograft tumor, targets pml, sulfur atoms, rationally developed, preclinical studies, oral bioavailability, novel arsenical, normal lines, mutated cancers, miraculous success, mice bearing, mediated pathway, maximally 127 |
| الوصف: | Arsenic trioxide (ATO) targets PML/RARα and leads to miraculous success in treating acute promyelocytic leukemia. Notably, ATO also targets p53, the most frequently mutated protein in cancers, through a similar binding mechanism. However, p53-targeting ATO trials are challenging due to the poor cellular uptake and cancer selectivity of ATO. Here, we analyzed the structure–activity relationship of arsenicals and rationally developed a novel arsenical (designated AcGlcAs) by conjugating arsenic to sulfur atoms and tetraacetyl-β-d-thioglucose. AcGlcAs exhibited remarkable cellular uptake through a thiol-mediated pathway (maximally 127-fold higher than ATO), thereby potently targeting PML/RARα and mutant p53. Among the 55 tested cell lines, AcGlcAs preferentially killed cancer lines rather than normal lines. In preclinical studies, AcGlcAs significantly extended the survival of mice bearing a xenograft tumor with p53 mutation while showing high plasma stability and oral bioavailability. Thus, AcGlcAs is a potential clinical candidate for precisely treating numerous p53-mutated cancers. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| العلاقة: | https://figshare.com/articles/journal_contribution/AcGlcAs_A_Novel_P53-Targeting_Arsenical_with_Potent_Cellular_Uptake_and_Cancer_Cell_Selectivity/24781865Test |
| DOI: | 10.1021/acs.jmedchem.3c00104.s001 |
| الإتاحة: | https://doi.org/10.1021/acs.jmedchem.3c00104.s001Test https://figshare.com/articles/journal_contribution/AcGlcAs_A_Novel_P53-Targeting_Arsenical_with_Potent_Cellular_Uptake_and_Cancer_Cell_Selectivity/24781865Test |
| حقوق: | CC BY-NC 4.0 |
| رقم الانضمام: | edsbas.C1609B59 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/acs.jmedchem.3c00104.s001 |
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