Discovery of meta-sulfamoyl N-hydroxybenzamides as HDAC8 selective inhibitors

In the past decade, although research and development of histone deacetylase (HDAC) inhibitors as therapeutic agents have achieved great accomplishments, especially in oncology field, there is still an urgent need for the discovery of isoform-selective HDAC inhibitors considering the side effects caused by nonselective HDAC inhibitors. HDAC8, a unique class I zinc-dependent HDAC, is becoming a potential target in cancer and other diseases. In the current study, a novel series of N-hydroxy-3-sulfamoylbenzamide-based HDAC8 selective inhibitors (12a-12p) were designed and synthesized, among which compounds 12a, 12b and 12c exhibited potent HDAC8 inhibition with two-digit nanomolar IC₅₀ values, and considerable selectivity over HDAC2 (>180-fold) and HDAC6 (∼30-fold) which was confirmed by western blot analysis. It is worth noting that 12a, 12b and 12c displayed highly selective anti-proliferative activity to T-cell leukemia cell lines Jurkat, Molt-4 and neuroblastoma cell line SK-N-BE-(2). Such selective cytotoxicity was also observed in the well-known HDAC8 selective inhibitor PCI-34051 but not in the pan-HDAC inhibitors SAHA and PXD101, indicating that HDAC8 selective inhibitor should have preferable benefit-risk profile in comparison with pan-HDAC inhibitor. Finally, the HDAC8 selectivity of 12a, 12b and 12c was rationalized by molecular docking study.