雌激素受体α（ERα）和组蛋白去乙酰化酶（HDACs）是有效的抗癌药物开发治疗靶点。联合使用多种ERα拮抗剂或降解剂和HDAC抑制剂的组合疗法已在基于ERα和HDAC途径之间的相互作用的内分泌耐药ER + 乳腺癌中证明有效。本研究报道了一系列甲氧基苯基或吡啶基替代的四氢异喹啉-羟酰胺的优化，这些化合物是由我们小组先前报道的具有双重ERα降解剂/HDAC抑制剂作用的31化合物优化得到的。大多数合成的化合物显示出强大的ERα降解效能和抗增殖活性。其中，A04表现出最佳的抗增殖活性（MCF-7 IC50 = 1.96 µM）和HDAC6抑制活性（HDAC6 IC50 = 25.96 nM），略微比31（MCF-7 IC50 = 4.38 μM，HDAC6 IC50 = 63.03 nM）的主导化合物更有效。此外，A04化合物在子宫内膜细胞中发挥出ERα独立的HDAC6抑制作用，没有促激活活性。这些结果表明A04是一种新的、有前途的双重ERα降解剂/HDAC抑制剂，值得进一步发展。 版权所有©2023 Elsevier Inc.

Both estrogen receptor α (ERα) and histone deacetylases (HDACs) are valid therapeutic targets for anticancer drug development. Combination therapies using diverse ERα antagonists or degraders and HDAC inhibitors have been proven effective in endocrine-resistant ER + breast cancers based on the crosstalk between ERα and HDAC pathway. In this study, we reported the optimization of a series of methoxyphenyl- or pyridinyl- substituted tetrahydroisoquinoline-hydroxamates, which were optimized from 31, a dual ERα degrader/HDAC inhibitor previously reported by our group. Most of the synthesized compounds displayed potent ERα degradation efficacy and antiproliferative activity. Among them, A04 demonstrated the best anti-proliferation activity (MCF-7 IC50 = 1.96 µM) and HDAC6 inhibitory activity (HDAC6 IC50 = 25.96 nM), which is slightly more potent than the lead compound 31 (MCF-7 IC50 = 4.38 μM, HDAC6 IC50 = 63.03 nM). In addition, compound A04 exerted ERα-independent HDAC6-inhibiting effect without agonistic activity in endometrial cells. These results demonstrated that A04 is a novel and promising dual ERα degrader/HDAC inhibitor worthy of further development.Copyright © 2023 Elsevier Inc. All rights reserved.