Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity

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 (1, 2) , Manfred Jung , Ina Oehme , Wolfgang Sippl

1 IGBMC - Institut de génétique et biologie moléculaire et cellulaire
2 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

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.

Domaines: Biochimie, Biologie Moléculaire

Salma Darwish, Ehab Ghazy, Tino Heimburg, Daniel Herp, Patrik Zeyen, et al.. Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity. International Journal of Molecular Sciences, 2022, 23 (14), ⟨10.3390/ijms23147535⟩. ⟨hal-04219177⟩