A5074742681- Protein Kinase Regulation and GTPase Signaling
- Genomics and Chromatin Dynamics
- Marine Sponges and Natural Products
- Mitochondrial Function and Pathology
- Epigenetics and DNA Methylation
- Alzheimer's disease research and treatments
- Viral-associated cancers and disorders
- Plant Virus Research Studies
- Cholinesterase and Neurodegenerative Diseases
- Peroxisome Proliferator-Activated Receptors
- Retinoids in leukemia and cellular processes
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Lymphoma Diagnosis and Treatment
- Cytomegalovirus and herpesvirus research
- Immune Response and Inflammation
- Marine Biology and Environmental Chemistry
- Neuropeptides and Animal Physiology
- RNA modifications and cancer
- Cancer-related gene regulation
- Acute Myeloid Leukemia Research
- Ubiquitin and proteasome pathways
- Neuroscience and Neuropharmacology Research
- Wnt/β-catenin signaling in development and cancer
- Organophosphorus compounds synthesis
Biogen (United States)
2016-2024
Stanford University
2011-2018
Colorado State University
2004-2010
Howard Hughes Medical Institute
2006
Dana-Farber Cancer Institute
2006
Harvard University
2006
Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) mediates viral genome attachment to mitotic chromosomes. We find that N-terminal LANA docks onto chromosomes by binding nucleosomes through the folded region of histones H2A-H2B. The same residues were required for both H2A-H2B and chromosome association. Further, did not bind Xenopus sperm chromatin, which is deficient in H2A-H2B; chromatin was rescued after assembly containing also describe...
Eukaryotic chromatin is highly dynamic and turns over rapidly even in the absence of DNA replication. Here we show that acidic histone chaperone nucleosome assembly protein 1 (NAP-1) from yeast reversibly removes replaces dimer H2A-H2B or variant dimers assembled nucleosomes, resulting active exchange. Transient removal facilitates sliding along to a thermodynamically favorable position. Histone exchange as well independent ATP relies on presence C-terminal domain NAP-1, though this region...
Interleukin receptor-associated kinase 4 (IRAK4) is a key node of signaling within the innate immune system that regulates production inflammatory cytokines and chemokines. The presence
The nuclear hormone receptor RORγ regulates transcriptional genes involved in the production of pro-inflammatory interleukin IL-17 which has been linked to autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. This activity is modulated through a protein-protein interaction involving activation function 2 (AF2) helix on ligand binding domain conserved LXXLL motif coactivator proteins. Our goal was develop specific inverse agonist that would help...
Structural analysis of the known NIK inhibitor 3 bound to kinase domain TTBK1 led design and synthesis a novel class azaindazole inhibitors exemplified by 8 (cell IC50: 571 nM). Systematic optimization this series analogs discovery 31, potent 315 nM) selective TTBK with suitable CNS penetration (rat Kp,uu: 0.32) for in vivo proof pharmacology studies. The ability 31 inhibit tau phosphorylation at disease-relevant Ser 422 epitope was demonstrated both mouse hypothermia rat developmental model...
We herein report the discovery, synthesis, and evolution of a series indazoles azaindazoles as CNS-penetrant IRAK4 inhibitors. Described is use structure-based property-based drug design strategically leveraged to guide property profile key into favorable space while maintaining potency selectivity. Our rationale that led toward functionalities with improvements, CNS-penetration, solubility, drug-like properties portrayed. In vivo evaluation an advanced analogue showed significant,...
Interleukin receptor associated kinase 4 (IRAK4) plays an important role in innate immune signaling through Toll-like and interleukin-1 receptors represents attractive target for the treatment of inflammatory diseases cancer. We previously reported development a potent, selective, brain-penetrant imidazopyrimidine series IRAK4 inhibitors. However, lead molecule BIO-7488 (1) suffered from low solubility which led to variable PK, compound accumulation, poor vivo tolerability. Herein, we...
AbstractKaposi's sarcoma-associated herpesvirus (KSHV) latently infects tumor cells and has an etiologic role in Kaposi's sarcoma, primary effusion lymphoma, multicentric Castleman's disease. Survival rapidly dividing depends on a carefully orchestrated chain of events. The viral genome, or episome, must replicate concert with cellular genetic material, then efficiently segregate to progeny nuclei. KSHV achieves this through its latency associated nuclear antigen (LANA), which simultaneously...
The evolution of cell-adhesion mechanisms in animals facilitated the assembly organized multicellular tissues. Studies traditional animal models have revealed two predominant adhesion structures, adherens junction (AJ) and focal adhesions (FAs), which are involved attachment neighboring cells to each other secreted extracellular matrix (ECM), respectively. AJ (containing cadherins catenins) FAs (comprising integrins, talin, paxillin) differ protein composition, but both junctions contain...
Glycogen synthase kinase 3 (GSK3) remains a therapeutic target of interest for diverse clinical indications. However, one hurdle in the development small molecule GSK3 inhibitors has been safety concerns related to pan-inhibition both paralogs, leading activation Wnt/β-catenin pathway and potential aberrant cell proliferation. Development GSK3α or GSK3β paralog-selective that could offer an improved profile reported but further advancement hampered by lack structural information GSK3α. Here...
Nucleostemin (NS) is a nucleolar-nucleoplasmic shuttle protein that regulates cell proliferation, binds p53 and Mdm2, highly expressed in tumor cells. We have identified NS as target of oxidative regulation transformed hematopoietic oligomerization occurs HL-60 leukemic cells Raji B lymphoblasts express high levels c-Myc intrinsic reactive oxygen species (ROS); reducing agents dissociate into monomers dimers. Exposure U2OS osteosarcoma with low ROS to hydrogen peroxide (H2O2) induces...
Phospholipase D (PLD) is a phospholipase enzyme responsible for hydrolyzing phosphatidylcholine into the lipid signaling molecule, phosphatidic acid, and choline. From therapeutic perspective, PLD has been implicated in human cancer progression as well target neurodegenerative diseases, including Alzheimer's. Moreover, knockdown of rescues ALS phenotype multiple Drosophila models (amyotrophic lateral sclerosis) displays modest motor benefits an SOD1 mouse model. To further validate whether...
Tau proteins play an important role in the proper assembly and function of neurons. Hyperphosphorylation tau by kinases such as tubulin kinase (TTBK) has been hypothesized to cause aggregation formation neurofibrillary tangles (NFTs) that lead destabilization microtubules, thereby contributing neurodegenerative diseases Alzheimer's disease (AD). There are two TTBK isoforms with highly homologous catalytic sites but distinct tissue distributions, phosphorylation patterns loss-of-function...
Autotaxin (ATX) is a lysophospholipase D that the main enzyme responsible for generating LPA in body fluids. Although ATX was isolated from conditioned medium of melanoma cells, later it discovered to play critical role vascular and neuronal development. has also been implicated primary brain tumor, fibrosis, rheumatoid arthritis, as well neurological diseases such multiple sclerosis, Alzheimer's disease, neuropathic pain. As levels are increased upon injury, selective inhibitor could...
Abstract Nucleostemin (NS) is a nucleolar-nucleoplasmic shuttle protein that key regulator of cell proliferation, binds p53 and Mdm2, highly expressed in tumor cells embryonic stem cells. We have identified NS as previously unreported target redox regulation transformed hematopoietic oligomerization present HL-60 leukemic Raji B lymphoblasts express high levels c-Myc intrinsic reactive oxygen species (ROS); exposure these to reducing agents including N-acetylcysteine results the dissociation...