Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity
In addition to involvement in epigenetic gene regulation, histone deacetylases (HDACs) regulate multiple cellular processes through mediating the activity of non-histone protein substrates. The knockdown of HDAC8 isozyme is associated with the inhibition of cell proliferation and apoptosis enhanceme...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-07-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/14/7535 |
| _version_ | 1797433532112437248 |
|---|---|
| author | Salma Darwish Ehab Ghazy Tino Heimburg Daniel Herp Patrik Zeyen Rabia Salem-Altintas Johannes Ridinger Dina Robaa Karin Schmidtkunz Frank Erdmann Matthias Schmidt Christophe Romier Manfred Jung Ina Oehme Wolfgang Sippl |
| author_facet | Salma Darwish Ehab Ghazy Tino Heimburg Daniel Herp Patrik Zeyen Rabia Salem-Altintas Johannes Ridinger Dina Robaa Karin Schmidtkunz Frank Erdmann Matthias Schmidt Christophe Romier Manfred Jung Ina Oehme Wolfgang Sippl |
| author_sort | Salma Darwish |
| collection | DOAJ |
| description | In addition to involvement in epigenetic gene regulation, histone deacetylases (HDACs) regulate multiple cellular processes through mediating the activity of non-histone protein substrates. The knockdown of HDAC8 isozyme is associated with the inhibition of cell proliferation and apoptosis enhancement in several cancer cell lines. As shown in several studies, HDAC8 can be considered a potential target in the treatment of cancer forms such as childhood neuroblastoma. The present work describes the development of proteolysis targeting chimeras (PROTACs) of HDAC8 based on substituted benzhydroxamic acids previously reported as potent and selective HDAC8 inhibitors. Within this study, we investigated the HDAC8-degrading profiles of the synthesized PROTACs and their effect on the proliferation of neuroblastoma cells. The combination of in vitro screening and cellular testing demonstrated selective HDAC8 PROTACs that show anti-neuroblastoma activity in cells. |
| first_indexed | 2024-03-09T10:18:18Z |
| format | Article |
| id | doaj.art-66232e6fc4624caa9371a7968efca1bb |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T10:18:18Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-66232e6fc4624caa9371a7968efca1bb2023-12-01T22:13:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-07-012314753510.3390/ijms23147535Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma ActivitySalma Darwish0Ehab Ghazy1Tino Heimburg2Daniel Herp3Patrik Zeyen4Rabia Salem-Altintas5Johannes Ridinger6Dina Robaa7Karin Schmidtkunz8Frank Erdmann9Matthias Schmidt10Christophe Romier11Manfred Jung12Ina Oehme13Wolfgang Sippl14Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), GermanyDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), GermanyDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), GermanyInstitute of Pharmaceutical Sciences, University of Freiburg, 79104 Freiburg, GermanyDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120 Heidelberg, GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120 Heidelberg, GermanyDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), GermanyInstitute of Pharmaceutical Sciences, University of Freiburg, 79104 Freiburg, GermanyDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), GermanyDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), GermanyDépartement de Biologie Structurale Intégrative, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, CEDEX, 67404 Illkirch, FranceInstitute of Pharmaceutical Sciences, University of Freiburg, 79104 Freiburg, GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120 Heidelberg, GermanyDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), GermanyIn addition to involvement in epigenetic gene regulation, histone deacetylases (HDACs) regulate multiple cellular processes through mediating the activity of non-histone protein substrates. The knockdown of HDAC8 isozyme is associated with the inhibition of cell proliferation and apoptosis enhancement in several cancer cell lines. As shown in several studies, HDAC8 can be considered a potential target in the treatment of cancer forms such as childhood neuroblastoma. The present work describes the development of proteolysis targeting chimeras (PROTACs) of HDAC8 based on substituted benzhydroxamic acids previously reported as potent and selective HDAC8 inhibitors. Within this study, we investigated the HDAC8-degrading profiles of the synthesized PROTACs and their effect on the proliferation of neuroblastoma cells. The combination of in vitro screening and cellular testing demonstrated selective HDAC8 PROTACs that show anti-neuroblastoma activity in cells.https://www.mdpi.com/1422-0067/23/14/7535histone deacetylases (HDACs)HDAC8proteolysis targeting chimera (PROTAC)neuroblastomasynthesis |
| spellingShingle | Salma Darwish Ehab Ghazy Tino Heimburg Daniel Herp Patrik Zeyen Rabia Salem-Altintas Johannes Ridinger Dina Robaa Karin Schmidtkunz Frank Erdmann Matthias Schmidt Christophe Romier Manfred Jung Ina Oehme Wolfgang Sippl Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity International Journal of Molecular Sciences histone deacetylases (HDACs) HDAC8 proteolysis targeting chimera (PROTAC) neuroblastoma synthesis |
| title | Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity |
| title_full | Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity |
| title_fullStr | Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity |
| title_full_unstemmed | Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity |
| title_short | Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity |
| title_sort | design synthesis and biological characterization of histone deacetylase 8 hdac8 proteolysis targeting chimeras protacs with anti neuroblastoma activity |
| topic | histone deacetylases (HDACs) HDAC8 proteolysis targeting chimera (PROTAC) neuroblastoma synthesis |
| url | https://www.mdpi.com/1422-0067/23/14/7535 |
| work_keys_str_mv | AT salmadarwish designsynthesisandbiologicalcharacterizationofhistonedeacetylase8hdac8proteolysistargetingchimerasprotacswithantineuroblastomaactivity AT ehabghazy designsynthesisandbiologicalcharacterizationofhistonedeacetylase8hdac8proteolysistargetingchimerasprotacswithantineuroblastomaactivity AT tinoheimburg designsynthesisandbiologicalcharacterizationofhistonedeacetylase8hdac8proteolysistargetingchimerasprotacswithantineuroblastomaactivity AT danielherp designsynthesisandbiologicalcharacterizationofhistonedeacetylase8hdac8proteolysistargetingchimerasprotacswithantineuroblastomaactivity AT patrikzeyen designsynthesisandbiologicalcharacterizationofhistonedeacetylase8hdac8proteolysistargetingchimerasprotacswithantineuroblastomaactivity AT rabiasalemaltintas designsynthesisandbiologicalcharacterizationofhistonedeacetylase8hdac8proteolysistargetingchimerasprotacswithantineuroblastomaactivity AT johannesridinger designsynthesisandbiologicalcharacterizationofhistonedeacetylase8hdac8proteolysistargetingchimerasprotacswithantineuroblastomaactivity AT dinarobaa designsynthesisandbiologicalcharacterizationofhistonedeacetylase8hdac8proteolysistargetingchimerasprotacswithantineuroblastomaactivity AT karinschmidtkunz designsynthesisandbiologicalcharacterizationofhistonedeacetylase8hdac8proteolysistargetingchimerasprotacswithantineuroblastomaactivity AT frankerdmann designsynthesisandbiologicalcharacterizationofhistonedeacetylase8hdac8proteolysistargetingchimerasprotacswithantineuroblastomaactivity AT matthiasschmidt designsynthesisandbiologicalcharacterizationofhistonedeacetylase8hdac8proteolysistargetingchimerasprotacswithantineuroblastomaactivity AT christopheromier designsynthesisandbiologicalcharacterizationofhistonedeacetylase8hdac8proteolysistargetingchimerasprotacswithantineuroblastomaactivity AT manfredjung designsynthesisandbiologicalcharacterizationofhistonedeacetylase8hdac8proteolysistargetingchimerasprotacswithantineuroblastomaactivity AT inaoehme designsynthesisandbiologicalcharacterizationofhistonedeacetylase8hdac8proteolysistargetingchimerasprotacswithantineuroblastomaactivity AT wolfgangsippl designsynthesisandbiologicalcharacterizationofhistonedeacetylase8hdac8proteolysistargetingchimerasprotacswithantineuroblastomaactivity |