Structural optimization of tetrahydroisoquinoline-hydroxamate hybrids as potent dual ERα degraders and HDAC inhibitors

• Published in: Bioorganic chemistry Vol. 134; p. 106459
• Main Authors: Xiong, Shuangshuang, Wang, Xin, Zhu, Meiqi, Song, Ke, Li, Yefan, Yang, Jiaqi, Liu, Xinyan, Liu, Mofei, Dong, Haijuan, Chen, Mingqi, Chen, Deying, Xiang, Hua, Luo, Guoshun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-05-2023
• Subjects: Antineoplastic Agents - chemistry; Breast cancer; Breast Neoplasms - drug therapy; Cell Line, Tumor; Cell Proliferation; Degrader; Estrogen receptor; Estrogen Receptor alpha - metabolism; Female; HDAC; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylases - metabolism; Humans; Hydroxamic Acids - pharmacology; Structure-Activity Relationship; Tetrahydroisoquinolines - pharmacology; Degrader; Estrogen receptor; Breast cancer; HDAC
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106459

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•A series of tetrahydroisoquinoline-hydroxamates as dual ERα degraders/HDAC inhibitors.•A04showed outstanding anti-proliferation activity and HDAC6 inhibitory activity.•A04 potently inhibited the ERα and HDAC6 signaling.
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.