Proteolysis-targeting chimeras and their implications in breast cancer

Tecalco-Cruz, Ángeles C.; Zepeda–Cervantes, Jesús; Ramírez-Jarquín, Josué O.; Rojas-Ochoa, Alberto

doi:10.37349/etat.2021.00060

Cited by 5 publications

(3 citation statements)

References 126 publications

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“…Hence, PROTACs bind to their target protein to promote its ubiquitination and degradation, and different PROTACs have been developed to degrade ERα via the UPS in breast cancer cells, exhibiting antitumor activity. PROTACs are being evaluated in patients with metastatic breast cancer and may become promising therapies ( 153 ). It is important to consider the implications of ERα stability in malignant mammary neoplasia to avoid some resistance to SERD or PROTAC treatments.…”

Section: Discussionmentioning

confidence: 99%

Decoding the Therapeutic Implications of the ERα Stability and Subcellular Distribution in Breast Cancer

et al. 2022

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Approximately 70% of all breast cancer cases are estrogen receptor-alpha positive (ERα+) and any ERα signaling pathways deregulation is critical for the progression of malignant mammary neoplasia. ERα acts as a transcription factor that promotes the expression of estrogen target genes associated with pro-tumor activity in breast cancer cells. Furthermore, ERα is also part of extranuclear signaling pathways related to endocrine resistance. The regulation of ERα subcellular distribution and protein stability is critical to regulate its functions and, consequently, influence the response to endocrine therapies and progression of this pathology. This minireview highlights studies that have deciphered the molecular mechanisms implicated in controlling ERα stability and nucleo-cytoplasmic transport. These mechanisms offer information about novel biomarkers, therapeutic targets, and promising strategies for breast cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Decoding the Therapeutic Implications of the ERα Stability and Subcellular Distribution in Breast Cancer

et al. 2022

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“…Importantly, a new therapy targeting ER degradation, such as proteolysis-targeting chimeric (PROTAC) technology, is being developed. It targets the regulation of ER stability via ubiquitylation, a therapeutic target for breast cancer [176,177].…”

Section: Post-translational Modifications Of Estrogen Receptorsmentioning

confidence: 99%

Estrogen Receptor Signaling in Breast Cancer

Miziak,

Baran,

Błaszczak

et al. 2023

Cancers

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Estrogen receptor (ER) signaling is a critical regulator of cell proliferation, differentiation, and survival in breast cancer (BC) and other hormone-sensitive cancers. In this review, we explore the mechanism of ER-dependent downstream signaling in BC and the role of estrogens as growth factors necessary for cancer invasion and dissemination. The significance of the clinical implications of ER signaling in BC, including the potential of endocrine therapies that target estrogens’ synthesis and ER-dependent signal transmission, such as aromatase inhibitors or selective estrogen receptor modulators, is discussed. As a consequence, the challenges associated with the resistance to these therapies resulting from acquired ER mutations and potential strategies to overcome them are the critical point for the new treatment strategies’ development.

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“…However, SERD molecules could not degrade ER completely, and long-term use can lead to drug resistance. PROTAC technology offers an alternative treatment option [133][134][135][136]. Arvinas developed an ER-targeting PROTAC, ARV-471 (Fig.…”

Section: Protacs For Targeting Nuclear Receptorsmentioning

confidence: 99%

An overview of PROTACs: a promising drug discovery paradigm

et al. 2022

Mol Biomed

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Proteolysis targeting chimeras (PROTACs) technology has emerged as a novel therapeutic paradigm in recent years. PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin–proteasome system. Currently, about 20–25% of all protein targets are being studied, and most works focus on their enzymatic functions. Unlike small molecules, PROTACs inhibit the whole biological function of the target protein by binding to the target protein and inducing subsequent proteasomal degradation. PROTACs compensate for limitations that transcription factors, nuclear proteins, and other scaffolding proteins are difficult to handle with traditional small-molecule inhibitors. Currently, PROTACs have successfully degraded diverse proteins, such as BTK, BRD4, AR, ER, STAT3, IRAK4, tau, etc. And ARV-110 and ARV-471 exhibited excellent efficacy in clinical II trials. However, what targets are appropriate for PROTAC technology to achieve better benefits than small-molecule inhibitors are not fully understood. And how to rationally design an efficient PROTACs and optimize it to be orally effective poses big challenges for researchers. In this review, we summarize the features of PROTAC technology, analyze the detail of general principles for designing efficient PROTACs, and discuss the typical application of PROTACs targeting different protein categories. In addition, we also introduce the progress of relevant clinical trial results of representative PROTACs and assess the challenges and limitations that PROTACs may face. Collectively, our studies provide references for further application of PROTACs.

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Proteolysis-targeting chimeras and their implications in breast cancer

Cited by 5 publications

References 126 publications

Decoding the Therapeutic Implications of the ERα Stability and Subcellular Distribution in Breast Cancer

Decoding the Therapeutic Implications of the ERα Stability and Subcellular Distribution in Breast Cancer

Estrogen Receptor Signaling in Breast Cancer

An overview of PROTACs: a promising drug discovery paradigm

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