Structural Optimization of 1,3-Diaryl-1,2,4-triazole-Capped Histone Deacetylase 6 Inhibitors to Obtain Novel Antiesophageal Cancer Candidates

Esophageal cancer, a leading global cancer, lacks effective therapies. Inhibition of histone deacetylase 6 (HDAC6) is a promising antitumor strategy, yet its role in esophageal cancer remains underexplored. Through structural optimization of our previously developed 1,3-diaryl-1,2,4-triazole-capped HDAC6 inhibitors, we identified compound 38k, exhibiting remarkably enhanced HDAC6 inhibition (IC₅₀ = 3.12 nM) and 352-fold selectivity over HDAC1. Molecular docking analysis, CETSA, and BLI confirmed its strong HDAC6 binding. Moreover, 38k displayed robust in vitro and in vivo antiesophageal cancer efficacy, along with an advantageous pharmacokinetic and safety profile. Notably, combining 38k with a PI3K inhibitor synergistically enhanced the efficacy (75.02% tumor growth inhibition vs 50.94% monotherapy), likely by counteracting HDAC6 inhibition-induced PI3K/AKT activation. These findings validate HDAC6 as a therapeutic target and highlight 38k as a promising candidate for esophageal cancer treatment, particularly in combination regimens.