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DOI: 10.1055/s-0036-1582523
Development of novel HDAC inhibitors to selectively co-inhibit HDAC8 and HDAC10 in childhood cancer
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.