Design and synthesis of thiolutin derived PSMD14/HDAC dual-target inhibitors against esophageal squamous cell carcinoma

Esophageal cancer is one of the most migratory, invasive, and lethal malignancies and has a poor prognosis, highlighting the urgent need to develop more effective drugs for its treatment. Given that PSMD14 and HDAC play an important role in the treatment of esophageal cancer, thiolutin is used as a lead compound to design and synthesize a series of dual-target PSMD14/HDAC small molecule inhibitors, aiming to discover more effective anti-esophageal cancer drugs. Through the in vitro screening of PSMD14/HDAC enzyme inhibitory activities of a series of thiolutin derivatives, it was found that compound 8b, with a linker length of 8 and a Zn²⁺-chelating group of 1,2-phenylenediamine, exhibited the most balanced inhibitory activity against PSMD14/HDAC.The impact of 8b on PSMD14/HDAC at the cellular level was evaluated, and its drug-like properties were further assessed in vivo. Compound 8b demonstrates balanced dual-target activity (PSMD14 IC₅₀ = 238.7 ± 27 nM, HDAC1 IC₅₀ = 141.2 ± 10.3 nM) and excellent cytotoxicity against esophageal cancer cells (IC₅₀ = 30–250 nM), effectively reversing epithelial-mesenchymal transition in cancer cells. Moreover, 8b exhibited excellent pharmacokinetic characteristics. More importantly, in a nude mouse xenograft model with subcutaneous transplantation of KYSE 30 cells, compound 8b (0.8 mg/kg, BID, PO, TGI = 81 %; 0.8 mg/kg, Q3D, SC, TGI = 77 %) significantly inhibited tumor growth, outperforming single-agent or combination treatments, thereby highlighting the therapeutic advantages of dual-target inhibition. These findings highlight the potential of dual-target PSMD14/HDAC inhibitors as a promising strategy for developing anti-esophageal cancer drugs.