Discovery of a Novel Class of PROTACs as Potent and Selective Estrogen Receptor α Degraders to Overcome Endocrine-Resistant Breast Cancer <i>In Vitro</i> and <i>In Vivo</i>

Xie, Baohua; Yin, Zhenggang; Hu, Zhigang; JunHui, Lv; Du, Chuanqian; Deng, Xiangping; Huang, Yuan; Li, Qiuzi; Huang, Jian; Liang, Kaiwei; Zhou, Hai-Bing; Dong, Chune

doi:10.1021/acs.jmedchem.2c02032

Cited by 12 publications

(7 citation statements)

References 54 publications

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“…In 2023, Xie et al disclosed a series of degradants based on the oxabicycloheptane sulfonamide (OBHSA) scaffold, among which compound ZD12 exhibited excellent anti-tumor efficacy and ERα degradation activity superior to Fluvastatin in both Tamoxifen-sensitive and -resistant breast cancer mouse models ( Burslem and Crews, 2020 ). However, there are still many challenges to be addressed, such as the low oral bioavailability of PROTACs, the occurrence of off-target effects, and the limited development of E3 ubiquitin ligases ( Garber, 2022 ; Xie et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Optimization of small molecule degraders and antagonists for targeting estrogen receptor based on breast cancer: current status and future

Yao,

Tao,

et al. 2023

Front. Pharmacol.

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The estrogen receptor (ER) is a classical receptor protein that plays a crucial role in mediating multiple signaling pathways in various target organs. It has been shown that ER-targeting therapies inhibit breast cancer cell proliferation, enhance neuronal protection, and promote osteoclast formation. Several drugs have been designed to specifically target ER in ER-positive (ER+) breast cancer, including selective estrogen receptor modulators (SERM) such as Tamoxifen. However, the emergence of drug resistance in ER+ breast cancer and the potential side effects on the endometrium which has high ER expression has posed significant challenges in clinical practice. Recently, novel ER-targeted drugs, namely, selective estrogen receptor degrader (SERD) and selective estrogen receptor covalent antagonist (SERCA) have shown promise in addressing these concerns. This paper provides a comprehensive review of the structural functions of ER and highlights recent advancements in SERD and SERCA-related small molecule drugs, especially focusing on their structural optimization strategies and future optimization directions. Additionally, the therapeutic potential and challenges of novel SERDs and SERCAs in breast cancer and other ER-related diseases have been discussed.

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Section: Discussionmentioning

confidence: 99%

Optimization of small molecule degraders and antagonists for targeting estrogen receptor based on breast cancer: current status and future

Yao,

Tao,

et al. 2023

Front. Pharmacol.

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“…Moreover, ERD-148 significantly downregulated the expression of an essential ER-regulated gene (GREB1) at 10 nM in various wildtype and mutant MCF-7 cell lines. Compound ZD12 was reported by Zhou et al [94] in 2023. Compound ZD12 was designed using a 7-oxabicyclo[2.2.1]heptane sulfonamide scaffold for ER, then attached to the VHL ligand through a five-carbon alkyl linker (Figure 7).…”

Section: Er Proteolysis-targeting Chimeras (Protacs)mentioning

confidence: 97%

New generation estrogen receptor-targeted agents in breast cancer: present situation and future prospectives

Min,

Liu,

Peng

et al. 2024

Acta Materia Medica

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Endocrine therapy that blocks estrogen receptor signaling has been effective for decades as a primary treatment choice for breast cancer patients expressing the estrogen receptor. However, the issue of drug resistance poses a significant clinical challenge. It is therefore critically important to create new therapeutic agents that can suppress ERα activity, particularly in cases of ESR1 mutations. This review highlights recent efforts in drug development of next generation ER-targeted agents, including oral selective ER degraders, proteolysis-targeting chimera ER degraders, and other innovative molecules, such as complete estrogen receptor antagonists and selective estrogen receptor covalent antagonists. The drug design, efficacy, and clinical trials for each compound are detailed herein.

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“…Common treatment approaches for breast cancer include surgery followed chemotherapy or radiotherapy, targeted therapy and immunotherapy, as well as endocrinetherapy. Tamoxifen, as a potent selective estrogen receptor modulator (SERM), has been reported to competitively bind to the estrogen receptor (ER) on tumor cells, thereby preventing the promotion of estrogen on tumor cell growth and proliferation [35]. However, Tamoxifen resistance remains a significant obstacle which lead to tumor relapse and metastasis in most of breast cancer patients, and there is no effective method to reverse Tamoxifen resistance in clinic[6].…”

Section: Introductionmentioning

confidence: 99%

Propofol overcome Tamoxifen resistance in breast cancer by modulating tumorogenesis, immune response and metabolism

Yin,

Gao,

Guo

et al. 2024

Preprint

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Although 70% of estrogen receptor (ER)-positive breast cancer patients benefit from Tamoxifen therapy, the developing resistance to Tamoxifen leads to high rates of metastasis and poor prognosis. Propofol, a commonly used anesthetic, has been shown to inhibit the occurrence and development of breast cancer. However, its role in anti-endocrine resistance in ER-positive breast cancer remains unclear. In this study, we found that Propofol significantly promotes cell cycle arrest, induces apoptosis, and inhibits proliferation in Tamoxifen-resistant breast cancer cells. Furthermore, transcriptome sequencing analysis revealed 1065 differentially expressed genes (DEGs) between Propofol-treated Tamoxifen-resistant MCF-7 (MCF7-TR) cells and none-treated MCF7-TR cells. Gene ontology annotation enrichment analysis (GO), Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis (KEGG), and gene set enrichment analysis (GSEA) showed that Propofol affects the expression of genes located in the plasma membrane and cell periphery, mainly regulating signals involved in cell cycle regulation, immune response modulation, and metabolism. Our results provide new insights into the mechanism by which Propofol controls resistance to Tamoxifen in breast cancer progression and offer a theoretical basis for clinical treatment.

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Discovery of a Novel Class of PROTACs as Potent and Selective Estrogen Receptor α Degraders to Overcome Endocrine-Resistant Breast Cancer In Vitro and In Vivo

Cited by 12 publications

References 54 publications

Optimization of small molecule degraders and antagonists for targeting estrogen receptor based on breast cancer: current status and future

Optimization of small molecule degraders and antagonists for targeting estrogen receptor based on breast cancer: current status and future

New generation estrogen receptor-targeted agents in breast cancer: present situation and future prospectives

Propofol overcome Tamoxifen resistance in breast cancer by modulating tumorogenesis, immune response and metabolism

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