Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1
| Autor: | Manfred Jung, Karin Schmidtkunz, Elizabeth R Morales, Stefan Günther, Wolfgang Sippl, Martin Hügle, Frank Erdmann, Patrik Zeyen, Ehab Ghazy, Dina Robaa, Christophe Romier, Matthias Schmidt, Daniel Herp |
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| Přispěvatelé: | Martin-Luther-Universität Halle Wittenberg (MLU), Albert-Ludwigs-Universität Freiburg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Romier, Christophe |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Bromodomain
[CHIM.THER]Chemical Sciences/Medicinal Chemistry MESH: Drug Design Histone Deacetylase 6 01 natural sciences MESH: Structure-Activity Relationship Drug Discovery MESH: Molecular Dynamics Simulation MESH: Histone Deacetylase Inhibitors 0303 health sciences biology Chemistry Acetylation General Medicine Hydroxamic acids 3. Good health Cell biology DNA-Binding Proteins Molecular Docking Simulation Leukemia Myeloid Acute Histone MESH: Repressor Proteins Epigenetics MESH: Leukemia Myeloid Acute MESH: Acetylation MESH: Cell Line Tumor [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication [CHIM.THER] Chemical Sciences/Medicinal Chemistry Antineoplastic Agents [SDV.CAN]Life Sciences [q-bio]/Cancer Molecular Dynamics Simulation Histone Deacetylases 03 medical and health sciences Structure-Activity Relationship [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication [SDV.CAN] Life Sciences [q-bio]/Cancer Cell Line Tumor MESH: Molecular Docking Simulation Humans Dual targeting inhibitors 030304 developmental biology Adaptor Proteins Signal Transducing MESH: Adaptor Proteins Signal Transducing Pharmacology Acute myeloid leukemia MESH: Humans 010405 organic chemistry Organic Chemistry HDAC8 HDAC6 0104 chemical sciences Histone Deacetylase Inhibitors Repressor Proteins MESH: Histone Deacetylases Docking (molecular) PHD finger BRPF1 Drug Design biology.protein MESH: Antineoplastic Agents MESH: Histone Deacetylase 6 MESH: DNA-Binding Proteins |
| Zdroj: | European Journal of Medicinal Chemistry European Journal of Medicinal Chemistry, 2020, 200, pp.112338. ⟨10.1016/j.ejmech.2020.112338⟩ European Journal of Medicinal Chemistry, Elsevier, 2020, 200, pp.112338. ⟨10.1016/j.ejmech.2020.112338⟩ |
| ISSN: | 0223-5234 1768-3254 |
| DOI: | 10.1016/j.ejmech.2020.112338⟩ |
| Popis: | International audience; Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemical and biophysical tests showed that compounds 23a,b and 37 are nanomolar inhibitors of both target proteins. Detailed structure-activity relationships were deduced for the synthesized inhibitors which were supported by extensive docking and molecular dynamics studies. Cellular testing in acute myeloid leukemia (AML) cells showed only a weak effect, most probably because of the poor permeability of the inhibitors. We also aimed to analyse the target engagement and the cellular activity of the novel inhibitors by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines. |
| Databáze: | OpenAIRE |
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