2. Academic Validation
  3. Structure-Based Design and Biological Characterization of Selective Histone Deacetylase 8 (HDAC8) Inhibitors with Anti-Neuroblastoma Activity

Structure-Based Design and Biological Characterization of Selective Histone Deacetylase 8 (HDAC8) Inhibitors with Anti-Neuroblastoma Activity

  • J Med Chem. 2017 Dec 28;60(24):10188-10204. doi: 10.1021/acs.jmedchem.7b01447.
Tino Heimburg 1,  Fiona R Kolbinger 2 3 4,  Patrik Zeyen 1,  Ehab Ghazy 1,  Daniel Herp 5,  Karin Schmidtkunz 5,  Jelena Melesina 1,  Tajith Baba Shaik 6,  Frank Erdmann 1,  Matthias Schmidt 1,  Christophe Romier 6,  Dina Robaa 1,  Olaf Witt 2 3 4 7,  Ina Oehme 2 3 4,  Manfred Jung 5,  Wolfgang Sippl 1
Affiliations

Affiliations

  • 1 Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg , 06120 Halle/Saale, Germany.
  • 2 Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) , INF 280, 69120 Heidelberg, Germany.
  • 3 German Consortium for Translational Cancer Research (DKTK) , 69120 Heidelberg, Germany.
  • 4 Preclinical Program, Hopp Children's Cancer Center at NCT Heidelberg (KiTZ) , 69120 Heidelberg, Germany.
  • 5 Institute of Pharmaceutical Sciences, University of Freiburg , 79104 Freiburg, Germany.
  • 6 Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), CNRS, INSERM, 67404 Illkirch Cedex, France.
  • 7 Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg Medical Center , 69120 Heidelberg, Germany.
PMID: 29190092 DOI: 10.1021/acs.jmedchem.7b01447
Abstract

Histone deacetylases (HDACs) are important modulators of epigenetic gene regulation and additionally control the activity of non-histone protein substrates. While for HDACs 1-3 and 6 many potent selective inhibitors have been obtained, for Other subtypes much less is known on selective inhibitors and the consequences of their inhibition. The present report describes the development of substituted benzhydroxamic acids as potent and selective HDAC8 inhibitors. Docking studies using available crystal structures have been used for structure-based optimization of this series of compounds. Within this study, we have investigated the role of HDAC8 in the proliferation of Cancer cells and optimized hits for potency and selectivity, both in vitro and in Cell Culture. The combination of structure-based design, synthesis, and in vitro screening to cellular testing resulted in potent and selective HDAC8 inhibitors that showed anti-neuroblastoma activity in cellular testing.

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