He Guoguo, Wu Zhenhui, Yang Xuan, Luo Xinrong, Zhang Lili, Du Zhenting, Li Shuwei, Wan Chuanxing
Key Laboratory of Conservation and Utilization of Biological Resources in the Tarim Basin, Alaer, Xinjiang 843300, PR China; College of Life Science and Technology, Tarim University, Alaer, Xinjiang 843300, PR China.
College of Chemical Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, PR China.
Bioorg Chem. 2025 Jul 1;161:108500. doi: 10.1016/j.bioorg.2025.108500. Epub 2025 Apr 26.
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 Zn-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 IC = 238.7 ± 27 nM, HDAC1 IC = 141.2 ± 10.3 nM) and excellent cytotoxicity against esophageal cancer cells (IC = 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.
食管癌是最具转移性、侵袭性和致死性的恶性肿瘤之一，预后较差，这凸显了开发更有效治疗药物的迫切需求。鉴于PSMD14和HDAC在食管癌治疗中发挥重要作用，硫藤黄菌素用作先导化合物来设计和合成一系列双靶点PSMD14/HDAC小分子抑制剂，旨在发现更有效的抗食管癌药物。通过对一系列硫藤黄菌素衍生物进行PSMD14/HDAC酶抑制活性的体外筛选，发现连接基团长度为8且锌螯合基团为1,2-苯二胺的化合物8b对PSMD14/HDAC表现出最平衡的抑制活性。评估了8b在细胞水平对PSMD14/HDAC的影响，并在体内进一步评估其类药性质。化合物8b表现出平衡的双靶点活性（PSMD14 IC = 238.7 ± 27 nM，HDAC1 IC = 141.2 ± 10.3 nM）以及对食管癌细胞优异的细胞毒性（IC = 30 - 250 nM），能有效逆转癌细胞的上皮-间质转化。此外，8b表现出优异的药代动力学特征。更重要的是，在皮下移植KYSE 30细胞的裸鼠异种移植模型中，化合物8b（0.8 mg/kg，每日两次，口服，肿瘤生长抑制率TGI = 81%；0.8 mg/kg，每三天一次，皮下注射，TGI = 77%）显著抑制肿瘤生长，优于单药或联合治疗，从而突出了双靶点抑制的治疗优势。这些发现凸显了双靶点PSMD14/HDAC抑制剂作为开发抗食管癌药物的一种有前景策略的潜力。
