Discovery and Development of a Selective Inhibitor of the ER Resident Chaperone Grp78.

A recent study illustrated that a fluorescence polarization assay can be used to identify substrate-competitive Hsp70 inhibitors that can be isoform-selective. Herein, we use that assay in a moderate-throughput screen and report the discovery of a druglike amino-acid-based inhibitor with reasonable specificity for the endoplasmic reticular Hsp70, Grp78. Using traditional medicinal chemistry approaches, the potency and selectivity were further optimized through structure-activity relationship (SAR) studies in parallel assays for six of the human Hsp70 isoforms.

CHML is an NRF2 target gene that regulates mTOR function.

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is often highly expressed in non-small cell lung cancer (NSCLC). Through its target genes, NRF2 enhances cancer progression and chemo/radioresistance, leading to a poorer prognosis in patients with high NRF2 expression. In this study, we identified CHM-like Rab escort protein (CHML; encoding Rep2) as an NRF2 target gene with an antioxidant response element (ARE) in its promoter region (-1622 to -1612).

The intricacies of NRF2 regulation in cancer.

The complex role of NRF2 in the context of cancer continues to evolve. As a transcription factor, NRF2 regulates various genes involved in redox homeostasis, protein degradation, DNA repair, and xenobiotic metabolism. As such, NRF2 is critical in preserving cell function and viability, particularly during stress.

Non-canonical NRF2 activation promotes a pro-diabetic shift in hepatic glucose metabolism.

Objective: NRF2, a transcription factor that regulates cellular redox and metabolic homeostasis, plays a dual role in human disease. While it is well known that canonical intermittent NRF2 activation protects against diabetes-induced tissue damage, little is known regarding the effects of prolonged non-canonical NRF2 activation in diabetes. The goal of this study was to determine the role and mechanisms of prolonged NRF2 activation in arsenic diabetogenicity.

FAM129B-dependent activation of NRF2 promotes an invasive phenotype in BRAF mutant melanoma cells.

Incidence of melanoma continues to rise in the United States with ~100,000 new cases diagnosed in 2019. While the 5-year survival rate of melanoma is 99% when localized, the rate of survival drops to 22.5% when distant disease is detected.

Activation of NRF2 by topical apocarotenoid treatment mitigates radiation-induced dermatitis.

Radiation therapy is a frontline treatment option for cancer patients; however, the effects of radiotherapy on non-tumor tissue (e.g. radiation-induced dermatitis) often worsen patient quality of life.

Chronic arsenic exposure enhances metastatic potential via NRF2-mediated upregulation of SOX9.

Chronic low dose arsenic exposure continues to be a worldwide health concern because of its prevalence and link to increased cancer risk, including non-small cell lung cancer (NSCLC). Mortality of NSCLC patients increases with the development of a metastatic lesion compared to when the tumor is localized; however, the exact mechanism for what causes NSCLC cells to metastasize in the context of environmental toxicant exposure has yet to be fully elucidated. One proposed contributor to metastasis in NSCLC is nuclear factor (erythroid-derived 2)-like 2 (NRF2), a transcription factor with known oncogenic properties that has proved to be critical for arsenic carcinogenesis.

Breakdown of an Ironclad Defense System: The Critical Role of NRF2 in Mediating Ferroptosis.

Ferroptosis is a non-apoptotic mode of regulated cell death that is iron and lipid peroxidation dependent. As new mechanistic insight into ferroptotic effectors and how they are regulated in different disease contexts is uncovered, our understanding of the physiological and pathological relevance of this mode of cell death continues to grow. Along these lines, a host of pharmacological modulators of this pathway have been identified, targeting proteins involved in iron homeostasis; the generation and reduction of lipid peroxides; or cystine import and glutathione metabolism.

Filtering through the role of NRF2 in kidney disease.

Kidney disease affects ~ 10% of the population worldwide, resulting in millions of deaths each year. Mechanistically, oxidative stress is a major driver of various kidney diseases, and promotes the progression from acute to chronic injury, as well as renal cancer development. NRF2, the master regulator of redox balance, has been shown to protect against kidney disease through its negation of reactive oxygen species (ROS).

A high throughput substrate binding assay reveals hexachlorophene as an inhibitor of the ER-resident HSP70 chaperone GRP78.

Glucose-regulated protein 78 (GRP78) is the ER resident 70 kDa heat shock protein 70 (HSP70) and has been hypothesized to be a therapeutic target for various forms of cancer due to its role in mitigating proteotoxic stress in the ER, its elevated expression in some cancers, and the correlation between high levels for GRP78 and a poor prognosis. Herein we report the development and use of a high throughput fluorescence polarization-based peptide binding assay as an initial step toward the discovery and development of GRP78 inhibitors. This assay was used in a pilot screen to discover the anti-infective agent, hexachlorophene, as an inhibitor of GRP78.

Redox regulation by NRF2 in aging and disease.

NRF2, a transcription factor that has been deemed the master regulator of cellular redox homeostasis, declines with age. NRF2 transcriptionally upregulates genes that combat oxidative stress; therefore, loss of NRF2 allows oxidative stress to go unmitigated and drive the aging phenotype. Oxidative stress is a common theme among the key features associated with the aging process, collectively referred to as the "Hallmarks of Aging", as it disrupts proteostasis, alters genomic stability, and leads to cell death.

Modulating NRF2 in Disease: Timing Is Everything.

The transcription factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) is a central regulator of redox, metabolic, and protein homeostasis that intersects with many other signaling cascades. Although the understanding of the complex nature of NRF2 signaling continues to grow, there is only one therapeutic targeting NRF2 for clinical use, dimethyl fumarate, used for the treatment of multiple sclerosis. The discovery of new therapies is confounded by the fact that NRF2 levels vary significantly depending on physiological and pathological context.

Kelch-like ECH-associated protein 1 (KEAP1) differentially regulates nuclear factor erythroid-2-related factors 1 and 2 (NRF1 and NRF2).

Nuclear factor erythroid-2-related factor 1 (NRF1) and NRF2 are essential for maintaining redox homeostasis and coordinating cellular stress responses. They are highly homologous transcription factors that regulate the expression of genes bearing antioxidant-response elements (AREs). Genetic ablation of or results in vastly different phenotypic outcomes, implying that they play different roles and may be differentially regulated.

ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A.

Activation of translation initiation is a common trait of cancer cells. Formation of the heterotrimeric eukaryotic initiation factor F (eIF4F) complex is the rate-limiting step in 5' m7GpppN cap-dependent translation. This trimeric complex includes the eIF4E cap binding protein, the eIF4G scaffolding protein, and the DEAD box RNA helicase eIF4A.