Novel hybrid conjugates with dual estrogen receptor α degradation and histone deacetylase inhibitory activities for breast cancer therapy

Autor: Lilan Xin, Chu Tang, Wentao Ning, Hai-Bing Zhou, Jian Huang, Zhiye Hu, Chenxi Zhao, Changhao Li
Rok vydání: 2021
Předmět:
Cell Survival
medicine.drug_class
medicine.medical_treatment
Clinical Biochemistry
Pharmaceutical Science
Estrogen receptor
Antineoplastic Agents
Breast Neoplasms
Protein degradation
01 natural sciences
Biochemistry
Histone Deacetylases
Targeted therapy
Structure-Activity Relationship
Breast cancer
Drug Discovery
medicine
Humans
Molecular Biology
Cell Proliferation
Sulfonamides
Dose-Response Relationship
Drug
Molecular Structure
Fulvestrant
010405 organic chemistry
Chemistry
Organic Chemistry
Histone deacetylase inhibitor
Estrogen Antagonists
Estrogen Receptor alpha
medicine.disease
0104 chemical sciences
Histone Deacetylase Inhibitors
010404 medicinal & biomolecular chemistry
MCF-7 Cells
Cancer research
Molecular Medicine
Female
Histone deacetylase
Drug Screening Assays
Antitumor
Tamoxifen
medicine.drug
Zdroj: Bioorganic & Medicinal Chemistry. 40:116185
ISSN: 0968-0896
DOI: 10.1016/j.bmc.2021.116185
Popis: Hormone therapy targeting estrogen receptors is widely used clinically for the treatment of breast cancer, such as tamoxifen, but most of them are partial agonists, which can cause serious side effects after long-term use. The use of selective estrogen receptor down-regulators (SERDs) may be an effective alternative to breast cancer therapy by directly degrading ERα protein to shut down ERα signaling. However, the solely clinically used SERD fulvestrant, is low orally bioavailable and requires intravenous injection, which severely limits its clinical application. On the other hand, double- or multi-target conjugates, which are able to synergize antitumor activity by different pathways, thus may enhance therapeutic effect in comparison with single targeted therapy. In this study, we designed and synthesized a series of novel dual-functional conjugates targeting both ERα degradation and histone deacetylase inhibiton by combining a privileged SERD skeleton 7-oxabicyclo[2.2.1]heptane sulfonamide (OBHSA) with a histone deacetylase inhibitor side chain. We found that substituents on both the sulfonamide nitrogen and phenyl group of OBHSA unit had significant effect on biological activities. Among them, conjugate 16i with N-methyl and naphthyl groups exhibited potent antiproliferative activity against MCF-7 cells, and excellent ERα degradation activity and HDACs inhibitory ability. A further molecular docking study indicated the interaction patterns of these conjugates with ERα, which may provide guidance to design novel SERDs or PROTAC-like SERDs for breast cancer therapy.
Databáze: OpenAIRE
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