A Modified HSP70 Inhibitor Shows Broad Activity as an Anticancer Agent
| العنوان: | A Modified HSP70 Inhibitor Shows Broad Activity as an Anticancer Agent |
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| المؤلفون: | Gao Zhang, Mark Andrake, Tim J. Yen, Donna L. George, Seth Hayik, Julia I-Ju Leu, Jessie Villanueva, Roland L. Dunbrack, Neil Beeharry, Meenhard Herlyn, Gregor M. Balaburski, Maureen E. Murphy |
| المصدر: | Molecular Cancer Research. 11:219-229 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Models, Molecular, Cancer Research, Antineoplastic Agents, HSP72 Heat-Shock Proteins, Plasma protein binding, Biology, Genomic Instability, Article, Substrate Specificity, Mice, Structure-Activity Relationship, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Animals, Humans, Cytotoxic T cell, Structure–activity relationship, Gene silencing, Computer Simulation, Binding site, Cytotoxicity, Molecular Biology, Sulfonamides, Gene Expression Regulation, Leukemic, Neoplasms, Experimental, Protein Structure, Tertiary, Molecular Docking Simulation, Oncology, Cancer cell, Cancer research, Anaphase-promoting complex, Protein Binding |
| الوصف: | The stress-induced HSP70 is an ATP-dependent molecular chaperone that plays a key role in refolding misfolded proteins and promoting cell survival following stress. HSP70 is marginally expressed in nontransformed cells, but is greatly overexpressed in tumor cells. Silencing HSP70 is uniformly cytotoxic to tumor but not normal cells; therefore, there has been great interest in the development of HSP70 inhibitors for cancer therapy. Here, we report that the HSP70 inhibitor 2-phenylethynesulfonamide (PES) binds to the substrate-binding domain of HSP70 and requires the C-terminal helical “lid” of this protein (amino acids 573–616) to bind. Using molecular modeling and in silico docking, we have identified a candidate binding site for PES in this region of HSP70, and we identify point mutants that fail to interact with PES. A preliminary structure–activity relationship analysis has revealed a derivative of PES, 2-(3-chlorophenyl) ethynesulfonamide (PES-Cl), which shows increased cytotoxicity and ability to inhibit autophagy, along with significantly improved ability to extend the life of mice with pre-B-cell lymphoma, compared with the parent compound (P = 0.015). Interestingly, we also show that these HSP70 inhibitors impair the activity of the anaphase promoting complex/cyclosome (APC/C) in cell-free extracts, and induce G2–M arrest and genomic instability in cancer cells. PES-Cl is thus a promising new anticancer compound with several notable mechanisms of action. Mol Cancer Res; 11(3); 219–29. ©2013 AACR. |
| تدمد: | 1557-3125 1541-7786 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3f7fa7d24fa64262b385d93cffc95268 https://doi.org/10.1158/1541-7786.mcr-12-0547-t |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....3f7fa7d24fa64262b385d93cffc95268 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573125 15417786 |
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