Structure-guided identification of novel dual-targeting estrogen receptor α degraders with aromatase inhibitory activity for the treatment of endocrine-resistant breast cancer

Xin, Lilan; Min, Jian; Hu, Hongliang; Li, Yuanyuan; Du, Chuanqian; Xie, Baohua; Cheng, Yan; Deng, Xiaofei; Deng, Xiangping; Shen, Kang; Huang, Jian; Chen, Chun‐Chi; Guo, Rey‐Ting; Dong, Chune; Zhou, Hai‐Bing

doi:10.1016/j.ejmech.2023.115328

Cited by 11 publications

(9 citation statements)

References 67 publications

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“…Simultaneously, the decline in estrogen biosynthesis could counteract SERMs’ agonistic effects on tissues like the uterus . Certain dual-targeting inhibitors ( 6 – 8 ) have been identified for the prevention of estrogen production or the inhibition of ER signal transduction in BC. − Although ERα/ARO dual-targeting drugs have not yet entered clinical trials, these studies have demonstrated the fundamental structural characteristics of ERα/ARO dual-targeting candidates, revealing that multitarget compounds may be feasible therapies for treating estrogen receptor-positive (ER + ) BC. Conversely, Ful stands as the initial FDA-approved SERD to exhibit clinical advantages in the management of patients dealing with advanced or metastatic ERα + BC.…”

Section: Introductionmentioning

confidence: 99%

“…One approach to address these challenges involves employing the pharmacophore fusion strategy, wherein two ligands are integrated into a single molecule, as we have previously demonstrated. 23 We hope this strategy will lead to a promising platform for TPD in patients receiving ER + BC therapy.…”

Section: ■ Introductionmentioning

confidence: 99%

“…However, far fewer dual-targeting PROTACs have been reported, probably due to their larger molecular weight and poorer drug-like properties caused by the requirement for an additional ligand. One approach to address these challenges involves employing the pharmacophore fusion strategy, wherein two ligands are integrated into a single molecule, as we have previously demonstrated . We hope this strategy will lead to a promising platform for TPD in patients receiving ER + BC therapy.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Novel ERα and Aromatase Dual-Targeting PROTAC Degraders to Overcome Endocrine-Resistant Breast Cancer

Xin,

Wang,

Cheng

et al. 2024

J. Med. Chem.

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Estrogen receptor α (ERα) plays a pivotal role in the proliferation, differentiation, and migration of breast cancer (BC) cells, and aromatase (ARO) is a crucial enzyme in estrogen synthesis. Hence, it is necessary to inhibit estrogen production or the activity of ERα for the treatment of estrogen receptor-positive (ER+) BC. Herein, we present a new category of dual-targeting PROTAC degraders designed to specifically target ERα and ARO. Among them, compound 18c bifunctionally degrades and inhibits ERα/ARO, thus effectively suppressing the proliferation of MCF-7 cells while showing negligible cytotoxicity to normal cells. In vivo, 18c promotes the degradation of ERα and ARO and inhibits the growth of MCF-7 xenograft tumors. Finally, compound 18c demonstrates promising antiproliferative and ERα degradation activity against the ERαMUT cells. These findings suggest that 18c, being the inaugural dual-targeting degrader for ERα and ARO, warrants further advancement for the management of BC and the surmounting of endocrine resistance.

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Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discovery of Novel ERα and Aromatase Dual-Targeting PROTAC Degraders to Overcome Endocrine-Resistant Breast Cancer

Xin,

Wang,

Cheng

et al. 2024

J. Med. Chem.

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“…Aloe vera, a well-known medicinal plant, has emerged as a promising candidate due to its diverse array of biologically active compounds. , These compounds exhibit potential in targeting ERα, offering new avenues for treatment, potentially with fewer side effects than existing medications like tamoxifen, raloxifene, and hydroxytamoxifen, which can cause side effects such as hot flashes, mood swings, and an increased risk of blood clots …”

Section: Introductionmentioning

confidence: 99%

A Virtual Drug Discovery Screening Illuminates Campesterol as a Potent Estrogen Receptor Alpha Inhibitor in Breast Cancer

Majumder,

Banerjee,

Mandal

et al. 2024

J. Med. Chem.

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Breast cancer remains a global health challenge, and innovative strategies are required to target estrogen receptor α (ERα), a key player in its development. This study investigates the potential of campesterol, a natural phytosterol, as an ERα inhibitor for breast cancer. Our approach integrates in silico, in vitro, and ex vivo experiments to assess the therapeutic potential of campesterol. In silico analyses highlight campesterol as a promising ERα ligand with favorable binding affinities and dynamic properties. Structural analysis reveals conformational changes in ERα upon campesterol binding. In vitro studies confirm the selective growth inhibition of campesterol against ERα-positive breast cancer cells. This study extends to ER+ breast cancer patient-derived organoids (PDOs), showing the effectiveness of campesterol in ERα-positive breast cancer PDOs. Importantly, it emphasizes the receptor-specific nature of campesterol, providing insights into its context-dependent action. In conclusion, campesterol displays potential as an ERα inhibitor, offering new avenues for ER+ breast cancer treatment.

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“…Other dual acting ligands were designed, selective estrogen receptor degraders/AI hybrids were developed, and they showed excellent ERα degradation activity, AI activity and remarkable antiproliferative activity against BC resistant cells. Thus, dual activity approach may lay the foundation of translational research for improved treatment of endocrine-resistant BC (Xin et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and in‐silico study of novel triarylethylene analogs with dual anti‐estrogenic and serotonergic activity

Mostafa,

Albeir,

Wober

et al. 2023

Drug Development Research

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Estrogen receptor is an important target in breast cancer. Serotonin receptors (5‐HT2A and 5‐HT2C, in particular) were investigated for a potential role in development and progression of breast cancer. Ligands that interact with estrogenic receptors influence the emotional state of females. Thus, designing selective estrogen receptor modulator (SERM) analogs with potential serotonergic activity is a plausible approach. The dual ligands can augment cytotoxic effect of SERMs, help in both physical and emotional menopausal symptom relief, enhance cognitive function and support bone health. Herein, we report triarylethylene analogs as potential candidates for treatment of breast cancer. Compound 2e showed (ERα relative β‐ galactosidase activity = 0.70), 5‐HT2A (Ki = 0.97 µM), and 5‐HT2C (Ki = 3.86 µM). It was more potent on both MCF‐7 (GI50 = 0.27 µM) and on MDA‐MB‐231 (GI50 = 1.86 µM) compared to tamoxifen (TAM). Compound 4e showed 40 times higher antiproliferative activity on MCF‐7 and 15 times on MDA‐MBA compared to TAM. Compound 4e had higher average potency than TAM on all nine tested cell line panels. Our in‐silico model revealed the binding interactions of compounds 2 and 2e in the three receptors; further structural modifications are suggested to optimize binding to the ERα, 5‐HT2A, and 5‐HT2C.

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Structure-guided identification of novel dual-targeting estrogen receptor α degraders with aromatase inhibitory activity for the treatment of endocrine-resistant breast cancer

Cited by 11 publications

References 67 publications

Discovery of Novel ERα and Aromatase Dual-Targeting PROTAC Degraders to Overcome Endocrine-Resistant Breast Cancer

Discovery of Novel ERα and Aromatase Dual-Targeting PROTAC Degraders to Overcome Endocrine-Resistant Breast Cancer

A Virtual Drug Discovery Screening Illuminates Campesterol as a Potent Estrogen Receptor Alpha Inhibitor in Breast Cancer

Design, synthesis, and in‐silico study of novel triarylethylene analogs with dual anti‐estrogenic and serotonergic activity

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