Ironing Out the Mechanism of gp130 Signaling.

gp130 functions as a shared signal-transducing subunit not only for interleukin (IL)-6 but also for eight other human cytokine receptor complexes. The IL-6 signaling pathway mediated through gp130 encompasses classical, trans, or cluster signaling, intricately regulated by a diverse array of modulators affecting IL-6, its receptor, and gp130. Currently, only a limited number of small molecule antagonists and agonists for gp130 are known.

An Intricate Relationship Between miR-155-5p Expression and Oxidative Stress in Bladder Cancer Patients Treated with Calmette-Guerin Immunotherapy.

Treatment failure after intravesical instillation of Bacillus Calmette-Guerin immunotherapy (BCG) for non-muscle-invasive bladder cancer (BCa) occurs frequently. The exact effects of BCG on cellular redox status and gene expression remain unclear. We assessed oxidative stress biomarkers and changes in miR-155-5p expression in response to BCG.

Aortic Injury Induced by Benzo(a)pyrene and Atherogenic Diet Increased Hepatic FGF21 Expression in C57BL/6J Mice.

Background: Benzo(a)pyrene (BaP), an environmental toxicant and endocrine disruptor, has been shown to exacerbate atherosclerosis when combined with a high-fat diet. Fibroblast Growth Factor-21 (FGF21), a novel hormone with anti-atherosclerotic properties, is associated with the presence of atherosclerosis and reduces plaque formation in experimental animals.

Objectives: The present study aimed to investigate the chronic effect of BaP injection on hepatic FGF21 expression, as an anti-atherosclerotic hormone, in mice fed with or without an atherogenic diet (AtD).

GRP78 inhibitor YUM70 upregulates 4E-BP1 and suppresses c-MYC expression and viability of oncogenic c-MYC tumors.

The 78-kDa glucose regulated protein (GRP78) commonly upregulated in a wide variety of tumors is an important prognostic marker and a promising target for suppressing tumorigenesis and treatment resistance. While GRP78 is well established as a major endoplasmic reticulum (ER) chaperone with anti-apoptotic properties and a master regulator of the unfolded protein response, its new role as a regulator of oncoprotein expression is just emerging. MYC is dysregulated in about 70 % of human cancers and is the most commonly activated oncoprotein.

Design of FK866-Based Degraders for Blocking the Nonenzymatic Functions of Nicotinamide Phosphoribosyltransferase.

Nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic target for treating select cancers. There are two forms of NAMPT: intracellular NAMPT (iNAMPT, the rate-limiting enzyme in the mammalian NAD main synthetic pathway) and extracellular NAMPT (eNAMPT, a cytokine with protumorigenic function). Reported NAMPT inhibitors only inhibit iNAMPT and show potent activities in preclinical studies.

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer.

Ferroptosis is a non-apoptotic form of cell death resulting from the iron-dependent accumulation of lipid peroxides. Colorectal cancer (CRC) cells accumulate high levels of intracellular iron and reactive oxygen species (ROS) and are thus particularly sensitive to ferroptosis. The compound (S)-RSL3 ([1S,3R]-RSL3) is a commonly used ferroptosis inducing compound that is currently characterized as a selective inhibitor of the selenocysteine containing enzyme (selenoprotein) Gluathione Peroxidase 4 (GPx4), an enzyme that utilizes glutathione to directly detoxify lipid peroxides.

Integrated transcriptomic and proteomic analysis reveals Guizhi-Fuling Wan inhibiting STAT3-EMT in ovarian cancer progression.

Background: Ovarian cancer (OC) is the most lethal gynecological malignancy. Frequent peritoneal dissemination is the main cause of low survival rate. Guizhi-Fuling Wan (GZFL) is a classical traditional Chinese herbal formula that has been clinically used for treating ovarian cancer with good outcome.

The application of PROTAC in HDAC.

Inducing protein degradation by proteolysis targeting chimera (PROTAC) has provided great opportunities for scientific research and industrial applications. Histone deacetylase (HDAC)-PROTAC has been widely developed since the first report of its ability to induce the degradation of SIRT2 in 2017. To date, ten of the eighteen HDACs (HDACs 1-8, HDAC10, and SIRT2) have been successfully targeted and degraded by HDAC-PROTACs.

First-in-Class NADH/Ubiquinone Oxidoreductase Core Subunit S7 (NDUFS7) Antagonist for the Treatment of Pancreatic Cancer.

Pancreatic cancer cells adapt to nutrient-scarce metabolic conditions by increasing their oxidative phosphorylation reserve to survive. Here, we present a first-in-class small-molecule NDUFS7 antagonist that inhibits oxidative phosphorylation (OXPHOS) for the treatment of pancreatic cancer. The lead compound, DX2-201, suppresses the proliferation of a panel of cell lines, and a metabolically stable analogue, DX3-213B, shows significant efficacy in a syngeneic model of pancreatic cancer.

Hyaluronic acid-bilirubin nanomedicine-based combination chemoimmunotherapy.

Despite significant advances in immune checkpoint blockade (ICB), immunosuppression mediated by tumor-associated myeloid cells (TAMCs) poses a major barrier to cancer immunotherapy. In addition, while immunogenic cell death (ICD) provides a viable approach to inducing anti-tumor immune response, it remains unknown how to effectively trigger ICD while addressing immunosuppressive TAMCs. Here, we show that SC144, a gp130 inhibitor that blocks the IL-6/gp130/STAT3 pathway, induces ICD of tumor cells and polarizes macrophages to M1-phenotype in vitro.

Chromium and lead levels and alteration in DDPH inhibition in patients with breast cancer undergoing chemotherapy.

Background: Recently the carcinogenic and toxic effects of some heavy metals such as chromium (Cr), and lead (Pb) through the mechanism of oxidative stress have been reported. Due to the various consequences of chemotherapeutic treatments on body hemostasis, the present study aimed to evaluate the effect of Adriamycin 60 mg/m and Cytoxan 600 mg/m (AC) chemotherapy on the serum levels of Cr, Pb, and the percent α-diphenyl-β-picrylhydrazyl (DPPH) inhibition.

Methods: This study was performed on 50 patients with breast cancer at two separate sampling times, the first at the initiation of chemotherapy and the last at the end of three courses of the AC chemotherapy treatment.

GRP78 Inhibitor YUM70 Suppresses SARS-CoV-2 Viral Entry, Spike Protein Production and Ameliorates Lung Damage.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has given rise to many new variants with increased transmissibility and the ability to evade vaccine protection. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum (ER) chaperone that has been recently implicated as an essential host factor for SARS-CoV-2 entry and infection. In this study, we investigated the efficacy of YUM70, a small molecule inhibitor of GRP78, to block SARS-CoV-2 viral entry and infection in vitro and in vivo.

Lipidation of a bioactive cyclotide-based CXCR4 antagonist greatly improves its pharmacokinetic profile in vivo.

The CXCR4 chemokine is a key molecular regulator of many biological functions controlling leukocyte functions during inflammation and immunity, and during embryonic development. Overexpression of CXCR4 is also associated with many types of cancer where its activation promotes angiogenesis, tumor growth/survival, and metastasis. In addition, CXCR4 is involved in HIV replication, working as a co-receptor for viral entry, making CXCR4 a very attractive target for developing novel therapeutic agents.

Design and Synthesis of Orally Active Quinolyl Pyrazinamides as Sigma 2 Receptor Ligands for the Treatment of Pancreatic Cancer.

Sigma 2 receptor (σ2R) is overexpressed in select cancers and is regarded as a biomarker for tumor proliferation. σ2R ligands are emerging as promising theranostics for cancer and neurodegenerative diseases. Herein, we describe the design and synthesis of a series of novel quinolyl pyrazinamides as selective and potent σ2R ligands that show sub-micromolar potency in pancreatic cancer cell lines.

Inhibition of Protein Disulfide Isomerase (PDIA1) Leads to Proteasome-Mediated Degradation of Ubiquitin-like PHD and RING Finger Domain-Containing Protein 1 (UHRF1) and Increased Sensitivity of Glioblastoma Cells to Topoisomerase II Inhibitors.

Glioblastoma (GBM) is the most aggressive brain tumor, and the prognosis remains poor with current available treatments. PDIA1 is considered a promising therapeutic target in GBM. In this study, we demonstrate that targeting PDIA1 results in increased GBM cell death by topoisomerase II (Top-II) inhibitors resulting in proteasome-mediated degradation of the oncogenic protein UHRF1.

Pyrazolone derivatives as potent and selective small-molecule SIRT5 inhibitors.

Sirtiun 5 (SIRT5) is a NAD-dependent protein lysine deacylase. It is emerging as a promising target for the development of drugs to treat cancer and metabolism-related diseases. In this study, we screened 5000 compounds and identified a hit compound 14 bearing a pyrazolone functional group as a novel SIRT5-selective inhibitor.

Inflammation as a chemoprevention target in asbestos-induced malignant mesothelioma.

Malignant mesothelioma (MM) is an incurable cancer of the serosal lining that is often caused by exposure to asbestos. Therefore, novel agents for the prevention and treatment of this disease are urgently needed. Asbestos induces the release of pro-inflammatory cytokines such as IL-1β and IL-6, which play a role in MM development.

Circulating plasma miR222-3P status and its potential diagnostic performance in prostate cancer.

Background: Although studies suggest that miR222-3p is dysregulated in prostate cancer (PC) cells and tissues, the possible changes in the level of miR222-3p in the plasma samples of PC patients remained unclear. The present study aimed to evaluate the diagnostic value of the plasma miR222-3p expression level as a potential biomarker in PC, benign prostatic hyperplasia (BPH) and healthy people.

Methods: Blood samples were collected from 100 adult males (54 patients with PC, 27 patients with BPH and 19 healthy individuals) referred to our affiliated hospital.

Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutations.

KRAS is the most commonly mutated oncogene in human cancers with limited therapeutic options, thus there is a critical need to identify novel targets and inhibiting agents. The 78-kDa glucose-regulated protein GRP78, which is upregulated in KRAS cancers, is an essential chaperone and the master regulator of the unfolded protein response (UPR). Following up on our recent discoveries that GRP78 haploinsufficiency suppresses both KRAS-driven pancreatic and lung tumorigenesis, we seek to determine the underlying mechanisms.

Identification of 2-hydroxybenzoic acid derivatives as selective SIRT5 inhibitors.

The sirtuin deacetylase SIRT5 plays important roles in regulating multiple metabolic pathways, and potentially represents an attractive target for the treatment of several human diseases, especially cancer. In this study, we report the identification of the hit compound 11 bearing a 2-hydroxybenzoic acid functional group as a novel SIRT5-selective inhibitor via our medium-throughput thermal shift screening assay. Hit 11 stabilizes SIRT5 in a dose-dependent manner and shows moderate inhibitory activity against SIRT5 and high subtype selectivity over SIRT1, 2, and 3 in a trypsin coupled enzyme-based assay.

Induction of Genes Implicated in Stress Response and Autophagy by a Novel Quinolin-8-yl-nicotinamide QN523 in Pancreatic Cancer.

Using a cytotoxicity-based phenotypic screen of a highly diverse library of 20,000 small-molecule compounds, we identified a quinolin-8-yl-nicotinamide, QN519, as a promising lead. QN519 represents a novel scaffold with drug-like properties, showing potent cytotoxicity in a panel of 12 cancer cell lines. Subsequently, lead optimization campaign generated compounds with IC values < 1 μM.

Multiparameter Optimization of Oxidative Phosphorylation Inhibitors for the Treatment of Pancreatic Cancer.

Targeting oxidative phosphorylation (OXPHOS) complexes is an emerging strategy to disrupt the metabolism of select cancer subtypes and to overcome resistance to targeted therapies. Here, we describe our lead optimization campaign on a series of benzene-1,4-disulfonamides as novel OXPHOS complex I inhibitors. This effort led to the discovery of compound () as one of the most potent complex I inhibitors reported to date.