Heat Shock Protein 70 Inhibitors. 2. 2,5′-Thiodipyrimidines, 5-(Phenylthio)pyrimidines, 2-(Pyridin-3-ylthio)pyrimidines, and 3-(Phenylthio)pyridines as Reversible Binders to an Allosteric Site on Heat Shock Protein 70
| العنوان: | Heat Shock Protein 70 Inhibitors. 2. 2,5′-Thiodipyrimidines, 5-(Phenylthio)pyrimidines, 2-(Pyridin-3-ylthio)pyrimidines, and 3-(Phenylthio)pyridines as Reversible Binders to an Allosteric Site on Heat Shock Protein 70 |
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| المؤلفون: | Alvin Lu, Gabriela Chiosis, Tony Taldone, Hardik J. Patel, Alexander Gozman, Y C Patel, Anna Rodina, Ronnie Maharaj, Cristina C. Clement, Maulik R. Patel, Pallav D. Patel, Jason C. Young, Yanlong Kang |
| المصدر: | Journal of Medicinal Chemistry |
| بيانات النشر: | American Chemical Society (ACS), 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Stereochemistry, Allosteric regulation, Covalent modification, Ligands, Combinatorial chemistry, Article, Hsp70, Structure-Activity Relationship, chemistry.chemical_compound, Pyrimidines, chemistry, Covalent bond, Drug Discovery, Molecular Medicine, Structure–activity relationship, HSP70 Heat-Shock Proteins, Pharmacophore, Allosteric Site, Derivative (chemistry), Cysteine |
| الوصف: | The discovery and development of heat shock protein 70 (Hsp70) inhibitors is currently a hot topic in cancer. In the preceding paper in this issue ( 10.1021/jm401551n ), we have described structure-activity relationship studies in the first Hsp70 inhibitor class rationally designed to bind to a novel allosteric pocket located in the N-terminal domain of the protein. These ligands contained an acrylamide to take advantage of an active cysteine embedded in the allosteric pocket and acted as covalent protein modifiers upon binding. Here, we perform chemical modifications around the irreversible inhibitor scaffold to demonstrate that covalent modification is not a requirement for activity within this class of compounds. The study identifies derivative 27c, which mimics the biological effects of the irreversible inhibitors at comparable concentrations. Collectively, the back-to-back manuscripts describe the first pharmacophores that favorably and selectively interact with a never explored pocket in Hsp70 and provide a novel blueprint for a cancer-oriented development of Hsp70-directed ligands. |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm401552y |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8290a2a3e182dbbfb0c1e2fc9f808198 https://doi.org/10.1021/jm401552y |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8290a2a3e182dbbfb0c1e2fc9f808198 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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| DOI: | 10.1021/jm401552y |