A Small Molecule Inhibits Deregulated NRF2 Transcriptional Activity in Cancer

Bollong, Michael J.; Yun, Hwayoung; Sherwood, Lance; Woods, Ashley K.; Lairson, Luke L.; Schultz, Peter G.

doi:10.1021/acschembio.5b00448

Cited by 76 publications

(75 citation statements)

References 18 publications

(58 reference statements)

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“…Certainly, specificity of activity for a particular transcription factor represents a challenge; for example, in the case of NRF2, brusatol, a quassinoid, has been reported to inhibit NRF2 signaling 36 , yet it has also has been shown to inhibit DNA, RNA, and protein synthesis as well as oxidative phosphorylation and c-myc activity in leukemia cells 37 . In addition, recently, a high-throughput screen of 30,000 compounds has led to the identification of NRF2 inhibitor, which has a selective response in cell lines with gain of NRF2 function 33 .…”

Section: Resultsmentioning

confidence: 99%

Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors

et al. 2016

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Loss of function mutations in Kelch Like ECH Associated Protein 1 (KEAP1) or gain-of-function mutations in nuclear factor erythroid 2-related factor 2 (NRF2) are common in non-small cell lung cancer (NSCLC) and is associated with therapeutic resistance. To discover novel NRF2 inhibitors for targeted therapy, we conducted a quantitative high-throughput screen using a diverse set of ~400,000 small molecules (Molecular Libraries Small Molecule Repository Library, MLSMR) at the National Center for Advancing Translational Sciences. We identified ML385 as a probe molecule that binds to NRF2 and inhibits its downstream target gene expression. Specifically, ML385 binds to the Neh1, the Cap ‘N’ Collar Basic Leucine Zipper (CNC-bZIP) domain of NRF2, and interferes with the binding of the V-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homolog G (MAFG)-NRF2 protein complex to regulatory DNA binding sequences. In clonogenic assays, when used in combination with platinum-based drugs such as doxorubicin or taxol, ML385 substantially enhances cytotoxicity in NSCLC cells compared to single agents alone. ML385 shows specificity and selectivity for NSCLC cells with KEAP1 mutation leading to gain of NRF2 function. In preclinical models of NSCLC with gain of NRF2 function, ML385 in combination with carboplatin showed significant anti-tumor activity. We demonstrate the discovery and validation of ML385 as a novel and specific NRF2 inhibitor and conclude that targeting NRF2 may represent a promising strategy for the treatment of advanced NSCLC.

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Section: Resultsmentioning

confidence: 99%

Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors

et al. 2016

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“…Western blotting was performed essentially as described previously (46). Cells were collected by brief trypsinization and centrifugation at 500 × g for 5 min.…”

Section: Methodsmentioning

confidence: 99%

A vimentin binding small molecule leads to mitotic disruption in mesenchymal cancers

Bollong

Pietilä

Pearson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Expression of the transcription factor FOXC2 is induced and necessary for successful epithelial-mesenchymal transition, a developmental program that when activated in cancer endows cells with metastatic potential and the properties of stem cells. As such, identifying agents that inhibit the growth of FOXC2-transformed cells represents an attractive approach to inhibit chemotherapy resistance and metastatic dissemination. From a high throughput synthetic lethal screen, we identified a small molecule, FiVe1, which selectively and irreversibly inhibits the growth of mesenchymally transformed breast cancer cells and soft tissue sarcomas of diverse histological subtypes. FiVe1 targets the intermediate filament and mesenchymal marker vimentin (VIM) in a mode which promotes VIM disorganization and phosphorylation during metaphase, ultimately leading to mitotic catastrophe, multinucleation, and the loss of stemness. These findings illustrate a previously undescribed mechanism for interrupting faithful mitotic progression and may ultimately inform the design of therapies for a broad range of mesenchymal cancers.vimentin | epithelial-to-mesenchymal transition | cancer stem cell | mitosis | drug discovery F or many tumor types, resistance to conventional chemotherapy and subsequent tumor relapse have been attributed to the presence of a slower cycling, drug-resistant population of cells termed cancer stem cells (CSCs) or tumor initiating cells. We and others have demonstrated that activation of a latent embryonic program, called the epithelial-mesenchymal transition (EMT), endows epithelial-derived cancer cells with the properties of stem cells as well as migratory and metastatic potential (1). Cells undergoing EMT exhibit the loss of epithelial cell-cell contacts (e.g., E-cadherin), the induction of matrix degrading proteases (e.g., matrix metalloproteinases), and the acquisition of motility-inducing intermediate filaments [e.g., vimentin (VIM)], features which promote metastatic progression by allowing dissemination from the local tumor niche (2). A number of transcription factors (e.g., Snail, Twist, ZEB1) and microenvironment-derived extracellular signaling molecules (e.g., TGF-β1) are capable of inducing the EMT transcriptional program. Among these factors, we have demonstrated that the transcription factor Forkhead Box C2 (FOXC2) is a central regulator of EMT in breast cancer (3, 4). FOXC2 expression is both up-regulated and required for the induction of CSC properties by the classical EMT-inducing factors Twist, Snail, and TGF-β1 (4

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“…This inhibitor was discovered in a screen utilizing MYC-3T3-ARE-LUC cells, which overexpress the oncogene c-Myc to drive Nrf2 levels past the suppressive ability of KEAP1. AEM1 decreased Nrf2 target gene transcription and acted synergistically with ROS-producing chemotherapy, although AEM1 treatment alone reduced tumor growth in vivo compared to control-treated mice [85]. AEM1 did not reduce Nrf2 levels, suggesting a KEAP1-independent mechanism.…”

Section: Targeting Nrf2 Signalingmentioning

confidence: 99%

Strange Bedfellows: Nuclear Factor, Erythroid 2-Like 2 (Nrf2) and Hypoxia-Inducible Factor 1 (HIF-1) in Tumor Hypoxia

Toth

Warfel

2017

Antioxidants

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The importance of the tumor microenvironment for cancer progression and therapeutic resistance is an emerging focus of cancer biology. Hypoxia, or low oxygen, is a hallmark of solid tumors that promotes metastasis and represents a significant obstacle to successful cancer therapy. In response to hypoxia, cancer cells activate a transcriptional program that allows them to survive and thrive in this harsh microenvironment. Hypoxia-inducible factor 1 (HIF-1) is considered the main effector of the cellular response to hypoxia, stimulating the transcription of genes involved in promoting angiogenesis and altering cellular metabolism. However, growing evidence suggests that the cellular response to hypoxia is much more complex, involving coordinated signaling through stress response pathways. One key signaling molecule that is activated in response to hypoxia is nuclear factor, erythroid 2 like-2 (Nrf2). Nrf2 is a transcription factor that controls the expression of antioxidant-response genes, allowing the cell to regulate reactive oxygen species. Nrf2 is also activated in various cancer types due to genetic and epigenetic alterations, and is associated with poor survival and resistance to therapy. Emerging evidence suggests that coordinated signaling through Nrf2 and HIF-1 is critical for tumor survival and progression. In this review, we discuss the distinct and overlapping roles of HIF-1 and Nrf2 in the cellular response to hypoxia, with a focus on how targeting Nrf2 could provide novel chemotherapeutic modalities for treating solid tumors.

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A Small Molecule Inhibits Deregulated NRF2 Transcriptional Activity in Cancer

Cited by 76 publications

References 18 publications

Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors

Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors

A vimentin binding small molecule leads to mitotic disruption in mesenchymal cancers

Strange Bedfellows: Nuclear Factor, Erythroid 2-Like 2 (Nrf2) and Hypoxia-Inducible Factor 1 (HIF-1) in Tumor Hypoxia

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