A5039663852- Metabolism, Diabetes, and Cancer
- Respiratory Support and Mechanisms
- Adipose Tissue and Metabolism
- Diet and metabolism studies
- Ubiquitin and proteasome pathways
- Genetic factors in colorectal cancer
- Genetics and Neurodevelopmental Disorders
- Intensive Care Unit Cognitive Disorders
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- Chronic Obstructive Pulmonary Disease (COPD) Research
- RNA modifications and cancer
- Nutrition, Genetics, and Disease
- Histone Deacetylase Inhibitors Research
- Nanoplatforms for cancer theranostics
- Down syndrome and intellectual disability research
- Photodynamic Therapy Research Studies
- Colorectal Cancer Treatments and Studies
- Hormonal Regulation and Hypertension
- Monoclonal and Polyclonal Antibodies Research
- Diabetic Foot Ulcer Assessment and Management
- Cardiac Fibrosis and Remodeling
- Cancer, Hypoxia, and Metabolism
- Plant Virus Research Studies
- TGF-β signaling in diseases
Vividion Therapeutics (United States)
2020-2024
Atkins (United States)
2024
Rigel (United States)
2002-2020
Sunesis (United States)
2014-2015
Stanford University
1996
National Institutes of Health
1985
The nuclear replication and retention functions of the Epstein–Barr virus (EBV) have been utilized here to maintain retroviral constructs episomally within human cell-based packaging lines. These hybrid EBV/retroviral are capable producing helper-free recombinant retrovirus as soon 48 hr for at least 30 days after transfection into 293T-based ecotropic and/or amphotropic cells. Viral titers greater than 107 TU/ml were obtained puromycin selection transfected This episomal approach production...
Ligand-induced protein degradation has emerged as a compelling approach to promote the targeted elimination of proteins from cells by directing these ubiquitin-proteasome machinery. So far, only limited number E3 ligases have been found support ligand-induced degradation, reflecting dearth E3-binding compounds for proteolysis-targeting chimera (PROTAC) design. Here, we describe functional screening strategy performed with focused library candidate electrophilic PROTACs discover bifunctional...
Inteins are polypeptide sequences found in a small set of primarily bacterial proteins that promote the splicing flanking pre-protein to generate mature protein products. can be engineered “split and inverted” configuration such product is cyclic consisting sequence linking two intein subdomains. We have split into retroviral expression system enable intracellular delivery library random peptides human cells. Cyclization could detected cell lysates using mass spectrometry. A functional...
Modulation of mitochondrial function through inhibiting respiratory complex I activates a key sensor cellular energy status, the 5'-AMP-activated protein kinase (AMPK). Activation AMPK results in mobilization nutrient uptake and catabolism for ATP generation to restore homeostasis. How these pathways are affected presence potent modulator role activation effects remain unclear. We have identified molecule, named R419, that vitro via inhibition at much lower concentrations than metformin...
Controlled mechanical ventilation (CMV) is associated with the development of diaphragm atrophy and contractile dysfunction, respiratory muscle weakness thought to contribute significantly delayed weaning patients. Therefore, therapeutic strategies for preventing these processes may have clinical benefit. The aim current study was investigate role Janus kinase (JAK)/signal transducer activator transcription 3 (STAT3) signaling pathway in CMV-mediated wasting rats. CMV-induced dysfunction...
Mechanical ventilation (MV) is one of the lynchpins modern intensive-care medicine and life saving in many critically ill patients. Continuous ventilator support, however, results ventilation-induced diaphragm dysfunction (VIDD) that likely prolongs patients' need for MV thereby leads to major associated complications avoidable intensive care unit (ICU) deaths. Oxidative stress a key pathogenic event development VIDD, but its regulation remains largely undefined. We report here JAK-STAT...
Intermittent claudication is a form of exercise intolerance characterized by muscle pain during walking in patients with peripheral artery disease (PAD). Endothelial cell and dysfunction are thought to be important contributors the etiology this disease, but lack preclinical models that incorporate these elements measure performance as primary end point has slowed progress finding new treatment options for patients. We sought develop an animal model vascular insufficiency which microvascular...
Skeletal muscle AMP-activated protein kinase (AMPK) is important for regulating glucose homeostasis, mitochondrial content and exercise capacity. R419 a complex-I inhibitor that has recently been shown to acutely activate AMPK in myotubes. Our main objective was examine whether treatment improves insulin sensitivity capacity obese resistant mice skeletal mediating potential effects.Glucose sensitivity, capacity, electron transport chain content/activity were examined wildtype (WT) β1β2...
Novel imidazole-based TGFβR1 inhibitors were identified and optimized for potency, selectivity, pharmacokinetic physicochemical characteristics. Herein, we report the discovery, optimization, evaluation of a potent, selective, orally bioavailable inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFβ-dependent cellular assays, excellent kinome favorable properties, curative vivo efficacy combination with anti-PD-1 antibody murine colorectal cancer (CRC)...
Abstract WRN helicase is a promising target for treating cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate cells faulty mismatch repair mechanisms. Currently, there are no approved drugs directly targeting human or RNA helicases, part the challenging nature of developing potent and selective compounds this class proteins. Here we describe chemical proteomic-enabled discovery clinical-stage, covalent...
Abstract The NRF2 transcription factor is constitutively active in cancer where it functions to maintain oxidative homeostasis and reprogram cellular metabolism. NRF2-active tumors exhibit NRF2-dependency resistance chemo/radiotherapy. Here we characterize VVD-065, a first-in-class inhibitor that acts via an unprecedented allosteric molecular glue mechanism. In the absence of stress or mutation, rapidly degraded by KEAP1-CUL3 ubiquitin-ligase complex. VVD-065 specifically covalently engages...
Respiratory dysfunction is prevalent in critically ill patients and can lead to adverse clinical outcomes, including respiratory failure increased mortality. muscles, which normally sustain respiration through inspiratory muscle contractions, become weakened during critical illness, recent studies suggest that weakness related systemic inflammation. Here, we investigate the pathophysiological role of inflammatory JAK1/3 signaling pathway diaphragm two distinct experimental models illness. In...
ABSTRACT A novel small-molecule inhibitor, referred to here as R706, was discovered in a high-throughput screen of chemical libraries against Huh-7-derived replicon cells carrying autonomously replicating subgenomic RNA hepatitis C virus (HCV). R706 highly potent blocking HCV replication measured by real-time reverse transcription-PCR and Western blotting R706-treated cells. Structure-activity iterations the series yielded lead compound, R803, that more specific for replication, with no...
Abstract RAS proteins are membrane bound GTPases that when hyperactivated, act as oncogenes through activation of the MAPK & PI3K pathways. Each these pathways has oncogenic potential, exemplified by high frequency BRAF mutations in melanoma and PIK3CA PTEN breast gynecological cancers. Simultaneous pathways, occurs driven cancers, generates aggressive cancers present a significant clinical challenge. KRAS, most commonly mutated isoform, is also frequently oncogene cancer. While...
Abstract The WRN helicase serves as a key target in the treatment of cancers characterized by microsatellite instability (MSI) because it plays crucial role resolving harmful non-canonical DNA structures that arise cells with defective mismatch repair systems. Despite critical functions human and RNA helicases, no drugs targeting these enzymes have been approved, largely due to difficulties identifying potent selective inhibitors. In this study, we present chemoproteomics-based...
Genetic disruption of the RAS binding domain (RBD) PI 3-kinase (PI3K) prevents growth mutant driven tumors in mice and does not impact PI3Ks role insulin mediated control glucose homeostasis. Selectively blocking RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid toxicity associated with inhibitors PI3K lipid kinase activity such alpelisib. Here we report compounds that bind covalently to cysteine 242 RBD p110a block ability...
Numerous human diseases can lead to atrophy of skeletal muscle, and loss this tissue has been correlated with increased mortality morbidity rates. Clinically addressing muscle remains an unmet medical need, the development preclinical tools assist drug discovery basic research in effort is important for advancing goal. In report, we describe a bioluminescent gene reporter rat, based on zinc finger nuclease-targeted insertion bicistronic luciferase into 3' untranslated region specific E3...
Abstract Introduction: Targeted protein degradation is a novel therapeutic modality that holds great promise. Current bispecific degraders have been mostly built using reversible ligands against two well characterized E3 ligases, CRBN and VHL. Features unique to each particular ligase, such as its tissue expression pattern or intrinsic catalytic efficiency could ultimately impact the in vivo bioactivity of any bifunctional drug based on it. Therefore, discovering E3s has potential enable new...
The 5′‐AMP‐activated protein kinase (AMPK) is a key regulator of energy homeostasis. Pharmacologic activation AMPK beneficial in treating metabolic disorders and improving exercise endurance. We previously identified small molecule activators that improved glucose tolerance running These compounds reduced cellular oxygen consumption increased AMP/ATP ADP/ATP ratios, demonstrating due to change status which results from altered mitochondrial respiration. Further biochemical studies showed the...
Abstract Nuclear factor erythroid 2-related 2 (NRF2) is a transcription that plays crucial role in various NRF2-dependent cancers. The protein levels of NRF2 are tightly controlled by specific E3 ligase complex composed Kelch-like ECH Associated Protein 1 (KEAP1), Cullin 3 (CUL3), and RING-box (RBX1). Under normal conditions, KEAP1 acts as an oxidative sensor facilitates the ubiquitination subsequent degradation NRF2. However, during or electrophilic stress, can be inactivated through...
Abstract Introduction: The KEAP1-nuclear factor erythroid 2-related 2 (NRF2) signaling axis is a key homeostatic mechanism for cells to maintain redox balance. In oxidative stress, reactive oxygen species (ROS) modify residues on KEAP1, impairing its binding and ubiquitination of NRF2. This leads an accumulation translocation NRF2 the nucleus where it increases transcription genes antioxidant response [Pillai 2022]. KEAP1-NRF2 pathway hijacked in cancers through gain function or KEAP1 loss...