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Glue-compounds search strategy. Figure based on the 6TTU structure from electron microscopy, showing an intermediate of the cullin-RING E3 ligase complex including β-TrCP and substrate IkBa.
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Drug resistance is one of the biggest challenges in cancer treatment and limits the potential to cure patients. In many tumors, sustained activation of the protein NRF2 makes tumor cells resistant to chemo- and radiotherapy. Thus, blocking inappropriate NRF2 activity in cancers has been shown to reduce resistance in models of the disease. There is...
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... a macromolecular assembly of the ubiquitination machinery involving β-TrCP ( Fig. 9) has been solved with cryo-electron microscopy (PDB 6TTU), showing an intermediate of the cullin-RING E3 ligase complex [139]. This complex catalyzes the ubiquitination of target proteins and subsequent proteasomal degradation. The complex includes β-TrCP, which is the protein responsible for recognizing and binding phosphorylated ...
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... The prolonged activation of the NRF2 protein in many cancers confers resistance to chemotherapy and radiation treatment on tumor cells. Therefore, it has been demonstrated that inhibiting aberrant NRF2 activity in malignancies lowers resistance in disease models (Srivastava et al. 2022). A general dependence on exogenous non-essential amino acids has been observed in cancers with strong antioxidant capacities. ...
Oxidative stress can affect the protein, lipids, and DNA of the cells and thus, play a crucial role in several pathophysiologi-cal conditions. It has already been established that oxidative stress has a close association with inflammation via nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway. Amino acids are notably the building block of proteins and constitute the major class of nitrogen-containing natural products of medicinal importance. They exhibit a broad spectrum of biological activities, including the ability to activate NRF2, a transcription factor that regulates endogenous antioxidant responses. Moreover, amino acids may act as synergistic antioxidants as part of our dietary supplementations. This has aroused research interest in the NRF2-inducing activity of amino acids. Interestingly, amino acids' activation of NRF2-Kelch-like ECH-associated protein 1 (KEAP1) signaling pathway exerts therapeutic effects in several diseases. Therefore, the present review will discuss the relationship between different amino acids and activation of NRF2-KEAP1 signaling pathway pinning their anti-inflammatory and antioxidant properties. We also discussed amino acids formulations and their applications as therapeutics. This will broaden the prospect of the therapeutic applications of amino acids in a myriad of inflammation and oxidative stress-related diseases. This will provide an insight for designing and developing new chemical entities as NRF2 activators.
... Compounds of this type are examples of molecular glues that can enhance or restore interactions between proteins for therapeutic purposes. There may be scope to expand the range of βTrCP-substrate interactions that can be targeted using this approach, this would be particularly interesting for the βTrCP-NRF2 interaction, to reduce NRF2 concentrations in cancer cells [66]. This is a further example of the use of βTrCP as a prototypical E3 ligase for new drug discovery approaches. ...
... βTrCP has a range of substrates that include both tumour suppressors and oncogenes. The current balance of opinion suggests that inhibition of βTrCP [66] activity is likely to have an antitumour effect in some cancers, a notion that is aligned with overexpression of the protein in some cancers. The identification of the role of βTrCP in the regulation of NRF2, a major regulator of redox processes in cells is relatively recent. ...
The E3 ligase beta-transducin repeat-containing protein (βTrCP) is an essential component of the ubiquitin-proteasome system that is responsible for the maintenance of cellular protein levels in human cells. Key target substrates for degradation include inhibitor of nuclear factor kappa B, programmed cell death protein 4 and forkhead box protein O3, alongside the transcription factor nuclear factor erythroid-2-related factor 2 (NRF2) that is responsible for cellular protection against oxidative damage. The tumour suppressive nature of many of its substrates and the overexpression of βTrCP observed in various cancers support a potential therapeutic role for inhibitors in the treatment of cancer. A small molecule substituted pyrazolone, GS143, and the natural product erioflorin have been identified as inhibitors of βTrCP and protect its targets from proteasomal degradation. Modified peptides based on the sequences of native substrates have also been reported with KD values in the nanomolar range. This review describes the current status of inhibitors of this E3 ligase. The scope for further inhibitor design and the development of PROTAC and molecular glue-type structures is explored in the context of βTrCP as an example of WD40 domain-containing proteins that are gaining attention as drug targets.
... Some recent studies have shown that alkaloids with NRF2 inhibitory activity can modulate cancer sensitivity for given chemotherapeutic agents and indirectly participate in cancer therapy [115,124,125]. Sustained activation of NRF2 can provoke resistance in chemotherapy on some tumor types, and in this view the degradation of β-transducin repeat-containing protein (β-TrCP)-NRF2 and KEAP1-NRF2 protein could be a potential methodology for enhancing chemosensitivity in cancer treatment [126]. The modulation of chemoresistance, a newly proposed mechanism, was investigated in a recent study where caffeine was examined as a purine alkaloid that decreases NRF2 levels (without affecting hypoxia-inducible factor-1α levels) and the expression of NRF2-targeted genes. ...
Being a controller of cytoprotective actions, inflammation, and mitochondrial function through participating in the regulation of multiple genes in response to stress-inducing endogenous or exogenous stressors, the transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) is considered the main cellular defense mechanism to maintain redox balance at cellular and tissue level. While a transient activation of NRF2 protects normal cells under oxidative stress, the hyperactivation of NRF2 in cancer cells may help them to survive and to adapt under oxidative stress. This can be detrimental and related to cancer progression and chemotherapy resistance. Therefore, inhibition of NRF2 activity may be an effective approach for sensitizing cancer cells to anticancer therapy. In this review, we examine alkaloids as NRF2 inhibitors from natural origin, their effects on cancer therapy, and/or as sensitizers of cancer cells to anticancer chemotherapeutics, and their potential clinical applications. Alkaloids, as inhibitor of the NRF2/KEAP1 signaling pathway, can have direct (berberine, evodiamine, and diterpenic aconitine types of alkaloids) or indirect (trigonelline) therapeutic/preventive effects. The network linking alkaloid action with oxidative stress and NRF2 modulation may result in an increased NRF2 synthesis, nuclear translocation, as well in a downstream impact on the synthesis of endogenous antioxidants, effects strongly presumed to be the mechanism of action of alkaloids in inducing cancer cell death or promoting sensitivity of cancer cells to chemotherapeutic agents. In this regard, the identification of additional alkaloids targeting the NRF2 pathway is desirable and the information arising from clinical trials will reveal the potential of these compounds as a promising target for anticancer therapy.
... Therefore, Nrf2 inhibitors may possess a potential risk of unintended side effects or toxicity. The lack of specificity can give rise to difficulty in identifying the exact mechanism by which they exert their effects [108]. Another limitation is the potency and bioavailability of natural product-derived Nrf2 inhibitors, which can vary widely. ...
Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates redox homeostasis, plays a pivotal role in several cellular processes such as cell proliferation and survival, and has been found to be aberrantly activated in many cancers. As one of the key oncogenes, Nrf2 represents an important therapeutic target for cancer treatment. Research has unraveled the main mechanisms underlying the Nrf2 pathway regulation and the role of Nrf2 in promoting tumorigenesis. Many efforts have been made to develop potent Nrf2 inhibitors, and several clinical trials are being conducted on some of these inhibitors. Natural products are well-recognized as a valuable source for development of novel therapeutics for cancer. So far, a number of natural compounds have been identified as Nrf2 inhibitors, such as apigenin, luteolin, and quassinoids compounds including brusatol and brucein D. These Nrf2 inhibitors have been found to mediate an oxidant response and display therapeutic effects in different types of human cancers. In this article, we reviewed the structure and function of the Nrf2/Keap1 system and the development of natural Nrf2 inhibitors with an emphasis on their biological function on cancer. The current status regarding the Nrf2 as a potential therapeutic target for cancer treatment was also summarized. It is hoped that this review will stimulate research on naturally occurring Nrf2 inhibitors as therapeutic candidates for cancer treatment.
... Under physiological conditions, elevated ROS levels impair the function of Keap1, promoting NRF2 nuclear translocation and the activation of its target gene transcription [38]. As the Keap1/NRF2 axis is disrupted in various cancers, it is a potential therapeutic target for cancer and chemoresistance [42,43]. Previous research has reported that the activation of the NRF2 signaling pathway by p62 occurs through the inhibition of Keap1, leading to increased expression of GCLC. ...
Globally, bladder cancer (BLCA) is still the leading cause of death in patients with tumors. The function and underlying mechanism of MTX-211, an EFGR and PI3K kinase inhibitor, have not been elucidated. This study examined the function of MTX-211 in BLCA cells using in vitro and in vivo assays. RNA sequencing, quantitative real-time polymerase chain reaction, Western blotting, co-immunoprecipitation, and immunofluorescence were performed to elucidate the underlying mechanism. Our observations revealed that MTX-211 has a time- and concentration-dependent inhibitory effect on bladder cancer cell proliferation. Flow cytometry analysis showed that cell apoptosis and G0/G1 cell cycle arrest were significantly induced by MTX-211. MTX-211 inhibited intracellular glutathione (GSH) metabolism, leading to a decrease in GSH levels and an increase in reactive oxygen species. GSH supplementation partly reversed the inhibitory effects of MTX-211. Further experiments verified that MTX-211 promoted NFR2 protein ubiquitinated degradation via facilitating the binding of Keap1 and NRF2, subsequently resulting in the downregulated expression of GCLM, which plays a vital role in GSH synthesis. This study provided evidence that MTX-211 effectively inhibited BLCA cell proliferation via depleting GSH levels through Keap1/NRF2/GCLM signaling pathway. Thus, MTX-211 could be a promising therapeutic agent for cancer.
... Indeed, a tumor-promoting role for NRF2 in cancer initiation has been reported, attributed to protection against redox stress in cells that have acquired mutations in KRAS and/or STK11 (Galan-Cobo et al., 2019). NRF2 activation can also promote chemoresistance (Purohit et al., 2021;Srivastava et al., 2022) and radiation resistance Koppula et al., 2022;Matsuoka et al., 2022), as well as metastasis. These disparate findings raise questions as to whether NRF2 is an oncogene, a tumor suppressor gene, or possibly both. ...
The oxidative balance of a cell is maintained by the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway. This cytoprotective pathway detoxifies reactive oxygen species and xenobiotics. The role of the KEAP1/NRF2 pathway as pro-tumorigenic or anti-tumorigenic throughout stages of carcinogenesis (including initiation, promotion, progression, and metastasis) is complex. This mini review focuses on key studies describing how the KEAP1/NRF2 pathway affects cancer at different phases. The data compiled suggest that the roles of KEAP1/NRF2 in cancer are highly dependent on context; specifically, the model used (carcinogen-induced vs genetic), the tumor type, and the stage of cancer. Moreover, emerging data suggests that KEAP1/NRF2 is also important for regulating the tumor microenvironment and how its effects are amplified either by epigenetics or in response to co-occurring mutations. Further elucidation of the complexity of this pathway is needed in order to develop novel pharmacological tools and drugs to improve patient outcomes.
... The NRF2 hyperactivation in cancer has sparked an interest in developing NRF2 inhibitors for cancer treatment and overcoming resistance to therapies. Multiple approaches have been used, including chemical library high-throughput screening (HTS), fragment-based nuclear magnetic resonance spectroscopy (NMR) screening, PROTACs, and molecular glues (86). Very recently, a chimeric molecule combining a CRBN ligand with an NRF2-binding portion was synthesized and shown to induce the degradation of the NRF2-MAFG heterodimer through the proteasome (87). ...
Nuclear factor erythroid 2-related factor 2 (NRF2; encoded by NFE2L2) is an inducible transcription factor that regulates the expression of a large network of genes encoding proteins with cytoprotective functions. NRF2 also has a role in the maintenance of mitochondrial and protein homeostasis, and its activation allows adaptation to numerous types of cellular stress. NRF2 is principally regulated at the protein stability level by three main ubiquitin ligase systems, of which the regulation by Kelch-like ECH-associated protein 1 (KEAP1), a substrate adaptor protein for Cul3/Rbx1-based ubiquitin ligase, is best understood. KEAP1 is a multi-functional protein and, in addition to being a substrate adaptor, it is a sensor for electrophiles and oxidants. Pharmacological inactivation of KEAP1 has protective effects in animal models of human disease, and KEAP1 is now widely recognized as a drug target, particularly for chronic diseases, where oxidative stress and inflammation underlie pathogenesis. Many compounds that target KEAP1 have been developed, including electrophiles that bind covalently to cysteine sensors in KEAP1, non-electrophilic protein-protein interaction inhibitors that bind to the Kelch domain of KEAP1, disrupting its interaction with NRF2, and most recently, heterobifunctional proteolysistargeting chimeras (PROTACs) that promote the proteasomal degradation of KEAP1. The drug development of KEAP1-targeting compounds has led to the entry of two compounds, dimethyl fumarate (BG-12, Tecfidera®) and RTA-408 (omaveloxolone, SKYCLARYS®), in clinical practice. In 2013, dimethyl fumarate was licenced as the first oral first-line therapy for relapsingremitting multiple sclerosis and is also used for the treatment of moderate-to-severe plaque psoriasis. In February 2023, omaveloxolone was approved by the United States Food and Drug Administration as the first and only drug for patients with Friedreich's ataxia.
... The dark side of NRF2 hyperactivation is most evident in cancer because NRF2 makes tumor cells resistant to chemo-, immuno-, and radiotherapy, highlighting the need for NRF2 inhibitors. The review by Srivastava et al. [18] approaches to inhibit NRF2 by enhancing with molecular glues its interaction with the main repressors KEAP1 and β-TrCP. ...
Drug resistance represents a significant obstacle in cancer treatment, underscoring the need for the discovery of novel therapeutic targets. Ubiquitin-specific proteases (USPs), a subclass of deubiquitinating enzymes, play a pivotal role in protein deubiquitination. As scientific research advances, USPs have been recognized as key regulators of drug resistance across a spectrum of treatment modalities, including chemotherapy, targeted therapy, immunotherapy, and radiotherapy. This comprehensive review examines the complex relationship between USPs and drug resistance mechanisms, focusing on specific treatment strategies and highlighting the influence of USPs on DNA damage repair, apoptosis, characteristics of cancer stem cells, immune evasion, and other crucial biological functions. Additionally, the review highlights the potential clinical significance of USP inhibitors as a means to counter drug resistance in cancer treatment. By inhibiting particular USP, cancer cells can become more susceptible to a variety of anti-cancer drugs. The integration of USP inhibitors with current anti-cancer therapies offers a promising strategy to circumvent drug resistance. Therefore, this review emphasizes the importance of USPs as viable therapeutic targets and offers insight into fruitful directions for future research and drug development. Targeting USPs presents an effective method to combat drug resistance across various cancer types, leading to enhanced treatment strategies and better patient outcomes.
