Design and synthesis of dual inhibitors targeting snail and histone deacetylase for the treatment of solid tumour cancer

Snail and histone deacetylases (HDACs) have an important impact on Cancer treatment, especially for their synergy. Therefore, the development of inhibitors targeting both Snail and HDAC might be a promising strategy for the treatment of cancers. In this work, we synthesized a series of Snail/HDAC dual inhibitors. Compound 9n displayed the most potent inhibitory activity against HDAC1 with an IC₅₀ of 0.405 μM, potent inhibition against Snail with a K_d of 0.180 μM, and antiproliferative activity in HCT-116 cell lines with an IC₅₀ of 0.0751 μM. Compound 9n showed a good inhibitory effect on NCI-H522 (GI₅₀ = 0.0488 μM), MDA-MB-435 (GI₅₀ = 0.0361 μM), and MCF7 (GI₅₀ = 0.0518 μM). Docking studies showed that compound 9n can be well docked into the active binding sites of Snail and HDAC. Further studies showed that compound 9n increased histone H4 acetylation in HCT-116 cells and decreased the expression of Snail protein to induce cell Apoptosis. These findings highlight the potential for the development of Snail/HDAC dual inhibitors as anti-solid tumour Cancer drugs.