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 <b>38k</b>, 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, <b>38k</b> displayed robust <i>in vitro</i> and <i>in vivo</i> antiesophageal cancer efficacy, along with an advantageous pharmacokinetic and safety profile. Notably, combining <b>38k</b> 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 <b>38k</b> as a promising candidate for esophageal cancer treatment, particularly in combination regimens.