Klin Padiatr 2016; 228 - A46
DOI: 10.1055/s-0036-1582523

Development of novel HDAC inhibitors to selectively co-inhibit HDAC8 and HDAC10 in childhood cancer

F Kolbinger 1, E Koeneke 1, J Senger 2, T Heimburg 3, T Bayer 3, M Jung 2, W Sippl 3, M Marek 4, C Romier 4, N Gunkel 5, AK Miller 5, P Sehr 6, O Witt 1, 7, 8, I Oehme 1
  • 1Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg
  • 2Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Freiburg
  • 3Institute of Pharmacy, Department of Medicinal Chemistry, Martin-Luther-University Halle-Wittenberg, Halle
  • 4Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), Illkirch-Graffenstaden, France
  • 5Cancer Drug Development, German Cancer Research Center (DKFZ), Heidelberg
  • 6EMBL-DKFZ-University of Heidelberg Chemical Biology Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg
  • 7Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg
  • 8Pediatric Oncology Program, National Center for Tumor Diseases (NCT), Germany

Introduction: Histone deacetylases (HDACs) are validated targets in antitumoral therapy, and five pan-HDAC inhibitors have been clinically approved to date. Dosage of these inhibitors is limited due to side effects (e.g. leukopenia, diarrhea, fatigue) mainly attributed to HDAC1, 2 and 3 inhibition. High HDAC8 and high HDAC10 co-expression correlate with exceptionally poor outcomes in neuroblastoma. Preliminary studies employing siRNAs or sub-class selective HDAC inhibitors support our hypothesis that HDAC8/10 co-inhibition may yield therapeutic advantages.

Results: To this end, ten novel small-molecule inhibitors were developed and assessed in various human pediatric cancer as well as non-transformed cell lines for HDAC8/10 specificity and antitumoral efficacy. These compounds were functionally characterized by means of target protein acetylation patterns as well as via phenotypic assays (e.g. acidic vesicle staining). Combined with conventional chemotherapeutic agents, cell viability was even further decreased. Conclusion: In order to assess suitability for future clinical trials, the most promising small-molecule inhibitor is currently being evaluated in a neuroblastoma xenograft model.