SERD-NHC-Au(I) complexes for dual targeting ER and TrxR to induce ICD in breast cancer

Lu, Yunlong; Sheng, Xinyu; Liu, Chao; Liang, Zhenlin; Wang, Xin; Liu, Lijuan; Wen, Zhenfan; Ye, Zhibin; Du, Qianming; Liu, Wukun

doi:10.1016/j.phrs.2023.106731

Cited by 14 publications

(6 citation statements)

References 65 publications

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“…This year Lu’s team modified G1T48, a clinical candidate SERD, by attaching it to the NHC-gold (I) complex as a dual-targeted drug targeting both the ER and an oxidoreductase, TrxR, and the experiments have shown that several of the compounds are highly effective. This study provides new insights and directions for future development strategies for SERDs, bringing investigators’ attention to dual-targeted drug development and the study of the ER signaling pathway ( Lu et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the optimization direction of SERDs and SERCAs is now expanding and becoming more diversified. New research and development efforts are exploring the potential of dual-targeted drugs that target ER and oxidoreductase enzymes simultaneously and combination therapies to regulate other alternative receptors or proteins implicated and ER as well ( Lu et al, 2023 ). By targeting multiple pathways or receptors simultaneously, the aim is to enhance the effectiveness and overcome potential resistance mechanisms of SERDs and SERCAs.…”

Section: Discussionmentioning

confidence: 99%

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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%

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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“…et al, 2020 45 in A2780 cells after 24 h incubation with 8 μM concentration (2/3 EC 50 ) reaching up to 25.0 ± 0.6 ng Au/10 6 cells. Next study involving the Au (NHC) complex, a SERD candidate G1T48 (NCT03455270), with a TrxR inhibitor-N-heterocyclic carbene gold(I) complex, 46 revealed the cellular uptake of Au into MCF-7 cells after 12 h of incubation reached up to 165 ± 7 ng/10 6 cells in cytoplasm and 183 ± 4 ng/10 6 cells in mitochondria. In contrast, in PC3 cells, dinuclear Au (NHC) complexes of the type Au 2 (RLOH)(PF 6 ) 2 (R = isopropyl or mesityl), bearing 2-hydroxyethane-1,1-diyl-bridged bis (imidazolylidene) ligands, 47 revealed the cellular uptake to cytosol only at ca.…”

Section: Cellular Uptake Of Gold Of the Selected Complexes In A2780 C...mentioning

confidence: 99%

Gold(I) N‐heterocyclic carbene (NHC) complexes containing 6‐mercaptopurine derivatives and their in vitro anticancer and anti‐inflammatory effects

Trávníček,

Vančo,

Čajan

et al. 2024

Applied Organom Chemis

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A series of eight N‐heterocyclic carbenes (NHC) gold(I) complexes, involving 1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene (iPr) ligand in combination with 6‐mercaptopurine derivatives (HL1–8), has been prepared and thoroughly characterized, including elemental analysis, mass spectrometry, infrared and multinuclear NMR spectroscopy, and single crystal X‐ray analysis. The complexes, showing general composition of [Au (iPr)(Ln)] 1–8, were evaluated for their in vitro cytotoxicity against four human cancer cell lines including A2780 (ovarian) and A2780R (ovarian Cisplatin resistant), PC3 (prostate) and MCF‐7 (breast), and normal human MRC‐5 cells (lung fibroblasts). The complexes revealed significant cytotoxicity, with the best IC50 values ≈ 3.4–6.4 μM against A2780 and reasonable selectivity. Cellular effects of the selected complexes on the A2780 cells were evaluated using various flow cytometry assays. Complexes 1, 3, and 4 showed a strong pro‐apoptotic effect and a strong effect on the loss of mitochondrial membrane potential. These findings indicate that their major mechanism of action is based on the collapse of the mitochondrial metabolism and activation of the intrinsic signaling pathway of apoptosis, consequently resulting in cell death. The complexes 1–8 revealed only negligible effect on the production of inflammatory‐related cytokine (TNF‐α), as well as the activation of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) or peroxisome proliferator‐activated receptor gamma (PPARγ). Moreover, the shotgun proteomic analysis was performed, and the obtained results suggest that the mechanism of action of complexes 1, 3, and 4 differs somewhat from that of Auranofin.

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“…146 Soon after, Liu and colleagues incorporated an 18β-glycyrrhetinic acid (GA) moiety (a pentacyclic triterpenoid compound with effective activity against cancer) into the imidazole ring of against MCF-7 cells in vitro and in vivo. 148 Moreover, Schobert and colleagues reported the good antiproliferative effect of a cationic triphenylphosphine gold−NHC complex 50 carrying a 4,5-diarylimidazole ligand. This complex was found to accumulate in mitochondria and exhibit strong ability to inhibit TrxR, leading to a distinct reduction of MMP and induction of apoptosis.…”

Section: Thioredoxin Reductase Inhibitionmentioning

confidence: 99%

A promising future of metal‐N‐heterocyclic carbene complexes in medicinal chemistry: The emerging bioorganometallic antitumor agents

Zhao,

Han,

Peng

et al. 2024

Medicinal Research Reviews

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Metal complexes based on N‐heterocyclic carbene (NHC) ligands have emerged as promising broad‐spectrum antitumor agents in bioorganometallic medicinal chemistry. In recent decades, studies on cytotoxic metal–NHC complexes have yielded numerous compounds exhibiting superior cytotoxicity compared to cisplatin. Although the molecular mechanisms of these anticancer complexes are not fully understood, some potential targets and modes of action have been identified. However, a comprehensive review of their biological mechanisms is currently absent. In general, apoptosis caused by metal–NHCs is common in tumor cells. They can cause a series of changes after entering cells, such as mitochondrial membrane potential (MMP) variation, reactive oxygen species (ROS) generation, cytochrome c (cyt c) release, endoplasmic reticulum (ER) stress, lysosome damage, and caspase activation, ultimately leading to apoptosis. Therefore, a detailed understanding of the influence of metal–NHCs on cancer cell apoptosis is crucial. In this review, we provide a comprehensive summary of recent advances in metal–NHC complexes that trigger apoptotic cell death via different apoptosis‐related targets or signaling pathways, including B‐cell lymphoma 2 (Bcl‐2 family), p53, cyt c, ER stress, lysosome damage, thioredoxin reductase (TrxR) inhibition, and so forth. We also discuss the challenges, limitations, and future directions of metal–NHC complexes to elucidate their emerging application in medicinal chemistry.

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SERD-NHC-Au(I) complexes for dual targeting ER and TrxR to induce ICD in breast cancer

Cited by 14 publications

References 65 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

Gold(I) N‐heterocyclic carbene (NHC) complexes containing 6‐mercaptopurine derivatives and their in vitro anticancer and anti‐inflammatory effects

A promising future of metal‐N‐heterocyclic carbene complexes in medicinal chemistry: The emerging bioorganometallic antitumor agents

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