Concomitant inhibition of estrogen receptor alpha (ERα) and histone deacetylase (HDAC) signaling has been proven effective in endocrine-resistant ER+ breast cancers. Herein, a series of tetrahydroisoquinoline (THIQ)-hydroxamate conjugates were rationally designed and synthesized as dual SERDs/HDAC inhibitors by incorporating the hydroxamate, a known HDAC pharmacophore, into a privileged THIQ scaffold of selective ERα degraders (SERDs). Some of these THIQ-hydroxamate conjugates displayed remarkable HDAC6 inhibition and improved antiproliferative activity against MCF-7 cells. Particularly, the most potent HDAC inhibitor 19k also exhibits potent ERα binding affinity, good ERα degradation efficacy and the best antiproliferative activity. Besides, 19k displayed superior antitumor efficacy than the drug combination (Fulvestrant + SAHA) through promoting ERα degradation and histone acetylation in an MCF-7 xenograft model, without causing observable toxicity. Collectively, this study validates the therapeutic potential of a dual-acting compound with potent ERα degradation efficacy and HDAC6 inhibition in breast cancer.

同时抑制雌激素受体α (ERα) 和组蛋白去乙酰化酶 (HDAC) 信号传导已被证明对内分泌耐药 ER+ 乳腺癌有效。在此，一系列四氢异喹啉 (THIQ)-异羟肟酸酯偶联物被合理设计并合成为双重 SERDs/HDAC 抑制剂，方法是将异羟肟酸酯（一种已知的 HDAC 药效团）结合到选择性 ERα 降解剂 (SERDs) 的特权 THIQ 支架中。其中一些 THIQ-异羟肟酸酯偶联物表现出显着的 HDAC6 抑制作用，并提高了对 MCF-7 细胞的抗增殖活性。特别是，最有效的 HDAC 抑制剂19k还表现出有效的 ERα 结合亲和力、良好的 ERα 降解效率和最佳的抗增殖活性。此外，19k通过在 MCF-7 异种移植模型中促进 ERα 降解和组蛋白乙酰化，显示出优于药物组合（氟维司群 + SAHA）的抗肿瘤功效，而不会引起可观察到的毒性。总的来说，这项研究验证了一种双效化合物在乳腺癌中的治疗潜力，该化合物具有有效的 ERα 降解功效和 HDAC6 抑制作用。