A5053713564- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Microtubule and mitosis dynamics
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Mitochondrial Function and Pathology
- Peptidase Inhibition and Analysis
- Extracellular vesicles in disease
- Melanoma and MAPK Pathways
- Protein Kinase Regulation and GTPase Signaling
- RNA Research and Splicing
- interferon and immune responses
- Pancreatic and Hepatic Oncology Research
- Biochemical and Molecular Research
- Advanced Proteomics Techniques and Applications
- Cancer-related Molecular Pathways
- Mosquito-borne diseases and control
- ATP Synthase and ATPases Research
- HIV Research and Treatment
- Congenital heart defects research
- Chronic Lymphocytic Leukemia Research
- Endoplasmic Reticulum Stress and Disease
- RNA and protein synthesis mechanisms
- Neuroscience and Neuropharmacology Research
- CAR-T cell therapy research
University of North Carolina at Chapel Hill
2017-2025
University of North Carolina Health Care
2017-2025
Communities In Schools of Orange County
2023
University of Utah
2022
University of California, Santa Cruz
2020
University of Southern Maine
2020
Federal Senate
2020
Translational Genomics Research Institute
2017
Mayo Clinic
2017
UNC Lineberger Comprehensive Cancer Center
2017
E-cigarettes vaporize propylene glycol/vegetable glycerin (PG/VG), nicotine, and flavorings. However, the long-term health effects of exposing lungs to vaped e-liquids are unknown.
ONC201 is a first-in-class imipridone molecule currently in clinical trials for the treatment of multiple cancers. Despite enormous potential, mechanism action controversial. To investigate and identify compounds with improved potency, we tested series novel analogues (TR compounds) effects on cell viability stress responses breast other cancer models. The TR were found to be ∼50–100 times more potent at inhibiting proliferation inducing integrated response protein ATF4 than ONC201. Using...
WDR5-degrader-E3 ligase ternary complex structure–based design led to a highly effective WDR5 degrader with robust in vivo antitumor activities.
Abstract Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by mutations 1,2 . RMC-7977 is highly selective inhibitor active GTP-bound forms KRAS, HRAS and NRAS, affinity for both mutant wild-type variants 3 More than 90% cases pancreatic ductal adenocarcinoma (PDAC) activating in KRAS 4 Here we assessed therapeutic comprehensive range PDAC models. We observed broad pronounced anti-tumour activity across models...
How the
To delineate the mechanisms by which ERK1 and ERK2 mitogen-activated protein kinases support mutant KRAS–driven cancer growth, we determined ERK-dependent phosphoproteome in KRAS-mutant pancreatic cancer. We that share near-identical signaling transforming outputs KRAS-regulated is driven nearly completely ERK. identified 4666 phosphosites on 2123 proteins, of 79 66%, respectively, were not previously associated with ERK, substantially expanding depth breadth phosphorylation events revealing...
Signal transducer and activator of transcription 3 (STAT3) is a key mediator intestinal inflammation tumorigenesis. However, the molecular mechanism that modulates STAT3 phosphorylation activation not fully understood. Here, we demonstrate modification with O-linked β-N-acetylglucosamine (O-GlcNAc) on threonine 717 (T717) negatively regulates its targets gene expression in macrophages. We further found cullin (CUL3), family E3 ubiquitin ligase, down-regulates O-GlcNAc transferase (OGT)...
Abstract TANK binding kinase 1 (TBK1) is an important involved in the innate immune response. Here we discover that TBK1 hyperactivated by von Hippel-Lindau (VHL) loss or hypoxia cancer cells. Tumors from patients with kidney VHL display elevated phosphorylation. Loss of via genetic ablation, pharmacologic inhibition, a new cereblon-based proteolysis targeting chimera specifically inhibits VHL-deficient cell growth, while leaving wild-type cells intact. depletion also significantly blunts...
We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF ERK (ERKi), is highly synergistic at low doses cell line, organoid, rat models PDAC, whereas each alone only cytostatic. Comprehensive mechanistic signaling studies using reverse phase protein array (RPPA)...
Nuclear receptor-binding SET domain-containing 2 (NSD2) plays important roles in gene regulation, largely through its ability to dimethylate lysine 36 of histone 3 (H3K36me2). Despite aberrant activity NSD2 reported numerous cancers, efforts selectively inhibit the catalytic this protein with small molecules have been unsuccessful date. Here, we report development UNC8153, a novel NSD2-targeted degrader that potently and reduces cellular levels both H3K36me2 chromatin mark. UNC8153 contains...
Bivalent chemical degraders, otherwise known as proteolysis-targeting chimeras (PROTACs), have proven to be an efficient strategy for targeting overexpressed or mutated proteins in cancer. PROTACs provide alternative approach small-molecule inhibitors, which are restricted by occupancy-driven pharmacology, often resulting acquired inhibitor resistance via compensatory increases protein expression. Despite the advantages of bivalent they suboptimal physicochemical properties and optimization...
ABSTRACT The actin cytoskeleton performs multiple cellular functions, and as such, polymerization must be tightly regulated. We previously demonstrated that reversible, non-degradative ubiquitylation regulates the function of polymerase VASP in developing neurons. However, underlying mechanism how impacts activity was unknown. Here, we show mimicking multi-monoubiquitylation at K240 K286 negatively interactions with actin. Using vitro biochemical assays, demonstrate reduced ability...
CDK9 inhibitors may treat KRAS-mutant cancers by inducing MYC protein degradation.
Alexander disease (AxD) is a fatal neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP), which supports the structural integrity of astrocytes. Over 70 GFAP missense cause AxD, but mechanism linking different to disease-relevant phenotypes remains unknown. We used AxD patient brain tissue and induced pluripotent stem cell (iPSC)-derived astrocytes investigate hypothesis that AxD-causing perturb key post-translational modifications (PTMs) on GFAP. Our...