Biotinylation of an acetylenic tricyclic bis(cyanoenone) lowers its potency as an NRF2 activator while creating a novel activity against BACH1

Moreno, Rita; Casares, Laura; Higgins, Maureen; Ali, Kevin X.; Honda, Tadashi; Wiel, Clotilde; Sayin, Volkan I.; Dinkova‐Kostova, Albena T.; Vega, Laureano de la

doi:10.1016/j.freeradbiomed.2022.08.041

Cited by 9 publications

(7 citation statements)

References 36 publications

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“…Considering that the main difference between the Keap1–Nrf2 ETGE interaction and the Keap1–Nrf2 DLGex interaction lies in the P6 subpocket, highlighting the P6 subpocket in drug design might hold enormous promise for the development of Keap1–Nrf2 inhibitors with better selectivity. , In addition, targeting the β-TrCP–Nrf2 pathway has been considered as an unexplored alternative to develop Nrf2 activators with higher target selectivity. ,, Recently, the first β-TrCP - Nrf2 PPI inhibitor has been successfully discovered, which represents a new direction for the future exploitation of safe and potent Nrf2 activators . Mounting evidence suggests that pharmacologic inhibition of BTB and CNC homology 1 (Bach1), a physiological repressor of Nrf2, also represents a promising approach to activate the Nrf2–ARE pathway without involving the electrophilic modification of cellular proteins. , In this regard, BACH1 inhibitors have opened the door for a new class of nonelectrophilic Nrf2 activators. , It is noteworthy that glycogen synthase kinase-3β (GSK-3β) can phosphorylate Nrf2, stimulating its association with β-TrCP and precipitating Nrf2 ubiquitination. , Therefore, GSK-3β inhibitors offer additional ways to activate Nrf2 without electrophilicity concerns. − More attention should be devoted to these areas. Furthermore, Nrf2 hyperactivation has been reported to be tightly related to the development of some other diseases, including but not limited to cancers, − bone hypoplasia, hydronephrosis, and aging acceleration .…”

Section: Discussionmentioning

confidence: 99%

“…146,147 In this regard, BACH1 inhibitors have opened the door for a new class of nonelectrophilic Nrf2 activators. 148,149 It is noteworthy that glycogen synthase kinase-3β (GSK-3β) can phosphorylate Nrf2, stimulating its association with β-TrCP and precipitating Nrf2 ubiquitination. 150,151 Therefore, GSK-3β inhibitors offer additional ways to activate Nrf2 without electrophilicity concerns.…”

Section: Discussionmentioning

confidence: 99%

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Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Protein–Protein Interaction Inhibitors

et al. 2023

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Oxidative stress has been implicated in a wide range of pathological conditions. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) exerts a central role in regulating the cellular defense system against oxidative and electrophilic insults. Nonelectrophilic inhibition of the protein−protein interaction (PPI) between Kelch-like ECH-associated protein 1 (Keap1) and Nrf2 has become a promising approach to activate Nrf2. Recently, multiple drug discovery strategies have facilitated the development of small-molecule Keap1−Nrf2 PPI inhibitors with potent activity and favorable drug-like properties. In this Perspective, we summarize the latest progress of small-molecule Keap1−Nrf2 PPI inhibitors from medicinal chemistry insights and discuss future prospects and challenges in this field.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Protein–Protein Interaction Inhibitors

et al. 2023

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“…However, the research on these BACH1 inhibitors is still at the stage of in vitro experiments or animal models, while their bioavailability and safety need to be further explored. HPP971 from VTV-Therapeutics and ML-0207/ASP8731 from Astellas-Pharma are in clinical development as BACH1 inhibitors [ 147 – 149 ]. HPP971 has completed two phase I studies and was well tolerated.…”

Section: Bach1 As a Therapeutic Targetmentioning

confidence: 99%

Transcription factor BACH1 in cancer: roles, mechanisms, and prospects for targeted therapy

Hu,

Zhang,

Luo

et al. 2024

Biomark Res

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Transcription factor BTB domain and CNC homology 1 (BACH1) belongs to the Cap ‘n’ Collar and basic region Leucine Zipper (CNC-bZIP) family. BACH1 is widely expressed in mammalian tissues, where it regulates epigenetic modifications, heme homeostasis, and oxidative stress. Additionally, it is involved in immune system development. More importantly, BACH1 is highly expressed in and plays a key role in numerous malignant tumors, affecting cellular metabolism, tumor invasion and metastasis, proliferation, different cell death pathways, drug resistance, and the tumor microenvironment. However, few articles systematically summarized the roles of BACH1 in cancer. This review aims to highlight the research status of BACH1 in malignant tumor behaviors, and summarize its role in immune regulation in cancer. Moreover, this review focuses on the potential of BACH1 as a novel therapeutic target and prognostic biomarker. Notably, the mechanisms underlying the roles of BACH1 in ferroptosis, oxidative stress and tumor microenvironment remain to be explored. BACH1 has a dual impact on cancer, which affects the accuracy and efficiency of targeted drug delivery. Finally, the promising directions of future BACH1 research are prospected. A systematical and clear understanding of BACH1 would undoubtedly take us one step closer to facilitating its translation from basic research into the clinic.

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“…In Figure 3B, the original compound TBE31 [ 57 ] is shown; TBE31, upon modification with biotin, is converted into a Bach1 inhibitor, compound TBE56, a 50 times stronger degrader of Bach1 than hemin itself. [ 58 ] CBD is a known Bach1 inhibitor, [ 59 ] and upon some chemical modification (introduction of a para‐quinone group), it also becomes a potent Nrf2 activator showing protection in cell models relevant to Huntington's disease. [ 60 ] A couple of papers published the benefits of Bach1 inhibitors in disease models.…”

Section: Introductionmentioning

confidence: 99%

Emerging small molecule inhibitors of Bach1 as therapeutic agents: Rationale, recent advances, and future perspectives

Hushpulian,

Kaidery,

Dutta

et al. 2023

BioEssays

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The transcription factor Nrf2 is the master regulator of cellular stress response, facilitating the expression of cytoprotective genes, including those responsible for drug detoxification, immunomodulation, and iron metabolism. FDA‐approved Nrf2 activators, Tecfidera and Skyclarys for patients with multiple sclerosis and Friedreich's ataxia, respectively, are non‐specific alkylating agents exerting side effects. Nrf2 is under feedback regulation through its target gene, transcriptional repressor Bach1. Specifically, in Parkinson's disease and other neurodegenerative diseases with Bach1 dysregulation, excessive Bach1 accumulation interferes with Nrf2 activation. Bach1 is a heme sensor protein, which, upon heme binding, is targeted for proteasomal degradation, relieving the repression of Nrf2 target genes. Ideally, a combination of Nrf2 stabilization and Bach1 inhibition is necessary to achieve the full therapeutic benefits of Nrf2 activation. Here, we discuss recent advances and future perspectives in developing small molecule inhibitors of Bach1, highlighting the significance of the Bach1/Nrf2 signaling pathway as a promising neurotherapeutic strategy.

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Biotinylation of an acetylenic tricyclic bis(cyanoenone) lowers its potency as an NRF2 activator while creating a novel activity against BACH1

Cited by 9 publications

References 36 publications

Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Protein–Protein Interaction Inhibitors

Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Protein–Protein Interaction Inhibitors

Transcription factor BACH1 in cancer: roles, mechanisms, and prospects for targeted therapy

Emerging small molecule inhibitors of Bach1 as therapeutic agents: Rationale, recent advances, and future perspectives

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