Development of novel tetrahydroisoquinoline-hydroxamate conjugates as potent dual SERDs/HDAC inhibitors for the treatment of breast cancer

Guoshun Luo; Xin Lin; Shengnan Ren; Shuangjie Wu; Xin Wang; Luyu Ma; Hua Xiang

doi:10.1016/j.ejmech.2021.113870

Development of novel tetrahydroisoquinoline-hydroxamate conjugates as potent dual SERDs/HDAC inhibitors for the treatment of breast cancer

Eur J Med Chem. 2021 Dec 15:226:113870. doi: 10.1016/j.ejmech.2021.113870. Epub 2021 Sep 25.

Authors

Guoshun Luo¹, Xin Lin², Shengnan Ren², Shuangjie Wu², Xin Wang², Luyu Ma², Hua Xiang³

Affiliations

¹ State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: gsluo@cpu.edu.cn.
² State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
³ State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: xianghua@cpu.edu.cn.

PMID: 34610548
DOI: 10.1016/j.ejmech.2021.113870

Abstract

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.

Keywords: Breast cancer; Conjugate; ERα degrader; HDAC inhibitor.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Development*
Drug Screening Assays, Antitumor
Estrogen Receptor alpha / antagonists & inhibitors
Estrogen Receptor alpha / metabolism
Female
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism
Humans
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology*
Mammary Neoplasms, Experimental / drug therapy
Mammary Neoplasms, Experimental / metabolism
Mammary Neoplasms, Experimental / pathology
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Structure-Activity Relationship
Tetrahydroisoquinolines / chemistry
Tetrahydroisoquinolines / pharmacology*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
ESR1 protein, human
Estrogen Receptor alpha
Histone Deacetylase Inhibitors
Hydroxamic Acids
Tetrahydroisoquinolines
1,2,3,4-tetrahydroisoquinoline
Histone Deacetylases