Discovery of 6-substituted indole and tetrahydroquinoline derivatives as selective HDAC8 inhibitors

The pursuit of isoform-selective histone deacetylase (HDAC) inhibitors is a promising strategy to overcome the adverse effects associated with pan-HDAC inhibitors. Through systematic structural modification of the known inhibitor PCI-34051, we designed and synthesized two novel series of compounds: 6-substituted indoles and 6-substituted tetrahydroquinolines. Among them, the tetrahydroquinoline derivative 11k exhibited potent HDAC8 inhibitory activity (IC₅₀ = 0.10 μM), and the indole derivative 5b also showed activity (IC₅₀ = 0.28 μM), both with excellent selectivity. Mechanistic studies revealed that these inhibitors specifically increased the acetylation of the HDAC8 substrate SMC3 in cells, without affecting histone H3 or α-tubulin acetylation, supporting their selective on-target action. Preliminary data indicated that compound 11k could modulate cytokine expression in T-cells, highlighting a potential non-cytotoxic biological effect that warrants further investigation. This work introduces novel chemotypes, notably the tetrahydroquinoline scaffold, for the development of selective HDAC8 inhibitors.