Efficacy of a New Selective Indole-based Histone Deacetylase 10 Inhibitor in Targeted Anticancer Therapy

Histone deacetylase (HDAC) inhibitors represent a newer class of anti-cancer agents that play a key role in both epigenetic and non-epigenetic regulation, leading to cancer cell death, apoptosis, and cell cycle arrest.. These inhibitors are being tested in numerous clinical trials against various diseases, including both hematological and solid malignancies. In the present study, we synthesized novel bicyclic hydroxamic acid derivatives and tested them in vitro against class I and IIb HDACs to investigate their inhibitory activity and selectivity. We demonstrate that compound 6 inhibits HDAC10 with high specificity over HDAC6, with no significant impact on class I HDACs. Compound 1 shows the best inhibitory activity against HDAC10, with IC ₅₀ 0.41 ± 0.02 nM. Compound 4 revealed a preference toward HDAC6, with an IC50 value of 2.5 ± 0.3 nM. Compounds 2 and 3 demonstrated high selectivity toward class IIb over class I HDACs. Docking and molecular dynamics studies revealed that compound 1 fits well into the active site of HDAC10, forming stable and strong interactions with key residues F204, D94, W205, and E274 in HDAC10. In addition, we tested these compounds against a panel of four human solid tumor cell lines. Furthermore, non-cancerous kidney cell lines (LLC-PK1 and VERO) were employed to determine the anti-cell proliferative activity of these compounds toward noncancerous cells.