A5102885067- Monoclonal and Polyclonal Antibodies Research
- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- Click Chemistry and Applications
- Synthesis and biological activity
- Computational Drug Discovery Methods
- Hepatitis C virus research
- Sirtuins and Resveratrol in Medicine
- Multiple Myeloma Research and Treatments
- DNA and Nucleic Acid Chemistry
- Psoriasis: Treatment and Pathogenesis
- Chemical Synthesis and Analysis
- RNA and protein synthesis mechanisms
- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- Advanced biosensing and bioanalysis techniques
- Protein Structure and Dynamics
- Protease and Inhibitor Mechanisms
- Cancer-related gene regulation
- Vitamin C and Antioxidants Research
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Cytokine Signaling Pathways and Interactions
- Chronic Lymphocytic Leukemia Research
- Histone Deacetylase Inhibitors Research
AbbVie (United States)
2015-2025
Abbott (United States)
2003-2010
Abbott Fund
2001-2010
Abbott (Germany)
2009
Dana-Farber Cancer Institute
2007-2008
Harvard University
2008
National Institutes of Health
2007
Discovery Laboratories (United States)
2006
Bangor University
1995-2002
Abbott (United Kingdom)
2000
Alzheimer's disease (AD) is a neurodegenerative disorder that linked to the presence of amyloid beta-peptides can form insoluble fibrils or soluble oligomeric assemblies. Soluble forms are present in brains and tissues patients, their correlates with progression. Long-lived be generated vitro by using small amounts aliphatic hydrocarbon chains detergents fatty acids preparations beta-peptides. Using NMR, we have characterized oligomers Abeta preglobulomer globulomer stable alter synaptic...
Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present collection chemical probes and associated reagents data to elucidate the function human murine PMTs in cellular studies. Our provides inhibitors antagonists that together modulate most key methylation marks on histones H3 H4, providing an important resource for modulating epigenomes. We describe comprehensive comparative characterization probe respect their...
While immune checkpoint blockade leads to potent antitumor efficacy, it also immune-related adverse events in cancer patients. These toxicities stem from systemic activation resulting inflammation of multiple organs, including the gastrointestinal tract, lung, and endocrine organs. We developed a dual variable domain immunoglobulin anti-CTLA4 antibody (anti-CTLA4 DVD, where CTLA4 is defined as cytotoxic T lymphocyte–associated antigen-4) possessing an outer tumor-specific antigen-binding...
The pituitary adenylate cyclase-activating polypeptide (PACAP) receptor is a class II G protein-coupled that contributes to many different cellular functions including neurotransmission, neuronal survival, and synaptic plasticity. solution structure of the potent antagonist PACAP (residues 6'-38') complexed N-terminal extracellular (EC) domain human splice variant hPAC1-R-short (hPAC1-R(S)) was determined by NMR. peptide adopts helical conformation when bound hPAC1-R(S) with bend at residue...
The molecular chaperone HSP90 has been shown to facilitate cancer cell survival by stabilizing key proteins responsible for a malignant phenotype. We report here the results of parallel fragment-based drug design approaches in novel inhibitors. Initial aminopyrimidine leads were elaborated using high-throughput organic synthesis yield nanomolar inhibitors enzyme. Second site also identified which bound two distinct conformations, an 'open' and 'closed' form. Intriguingly, linked fragment...
Small-molecule (SM) leads in the early drug discovery pipeline are progressed primarily based on potency against intended target(s) and selectivity a very narrow slice of proteome. So, why is there tendency to wait until SMs matured before probing for deeper mechanistic understanding? For one, concern about interpretation complex -omic data outputs resources needed test these hypotheses. However, with recent advances broad endpoint profiling assays that have companion reference databases...
Abstract IL-36 cytokines are pro-inflammatory members of the IL-1 family that upregulated in inflammatory disorders. Specifically, IL-36γ is highly expressed active psoriatic lesions and can drive processes 3D human skin equivalents supporting a role for this target inflammation. Small molecule antagonists interleukins have been historically challenging to generate. Nevertheless, we performed small high-throughput screen identify using novel TR-FRET binding assay. Several compounds,...
Targeted protein degradation (TPD) is a therapeutic approach that leverages the cell's natural machinery to degrade targets instead of inhibiting them. This accomplished by using mono- or bifunctional small molecules designed induce proximity target proteins and E3 ubiquitin ligases, leading ubiquitination subsequent proteasome-dependent target. One most significant attributes TPD its proposed catalytic mechanism action, which permits substoichiometric exposure achieve desired...
Affinity capture (AC) combined with mass spectrometry (MS)-based proteomics is highly utilized throughout the drug discovery pipeline to determine small-molecule target selectivity and engagement. However, tedious sample preparation steps time-consuming MS acquisition process have limited its use in a high-throughput format. Here, we report an automated workflow employing biotinylated probes streptavidin magnetic beads for enrichment 96-well plate format, ending direct sampling from EvoSep...
IL-36 cytokines signal through the receptor (IL-36R) and a shared subunit, IL-1RAcP (IL-1 accessory protein). The activation mechanism for pathway is proposed to be similar that of IL-1 in an IL-36R agonist (IL-36α, IL-36β, or IL-36γ) forms binary complex with IL-36R, which then recruits IL-1RAcP. Recent studies have shown interacts even absence agonist. To elucidate mechanism, we considered all possible binding events ligands/receptors examined these direct assays. Our results indicated...
Tumor necrosis factor α (TNFα) is a soluble cytokine that directly involved in systemic inflammation through the regulation of intracellular NF-κB and MAPK signaling pathways. The development biologic drugs inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis other chronic autoimmune diseases; however, proven be difficult drug small molecules. Herein, we present two-phase, fragment-based discovery (FBDD) effort which first identified isoquinoline...
Cancer cells are highly reliant on NAD+-dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ salvage from nicotinamide, has been investigated as a target anticancer therapy. Known NAMPT inhibitors with potent cell activity composed nitrogen-containing aromatic group, which is phosphoribosylated by enzyme. Here, we identified two novel types...
Structure-function studies of antibody-antigen systems include the identification amino acid residues in antigen that interact with an antibody and elucidation their individual contributions to binding affinity. We used fluorescence correlation spectroscopy (FCS) alanine-scanning mutagenesis characterize interactions brain natriuretic peptide (BNP) two monoclonal antibodies. Human BNP is a 32 residue long cyclic polypeptide ring structure confined between cysteines positions 10 26. It...
Ligand-binding assays are the linchpin of drug discovery and medicinal chemistry. Cell-surface receptors their ligands have traditionally been characterized by radioligand-binding assays, which low temporal spatial resolution entail safety risks. Here, we report a powerful alternative (GlycoFRET), where terbium-labeled fluorescent reporters irreversibly attached to metabolic glycan engineering. For first time, show time-resolved fluorescence resonance energy transfer between receptor glycans...
A novel and innovative high-throughput screening assay was developed to identify both activators inhibitors of AMP-activated protein kinase (AMPK) using microarrayed compound (microARCS) technology. Test compounds were arrayed at a density 8640 on polystyrene sheet, the enzyme peptide substrate introduced into by incorporating them an agarose gel followed placement gels onto sheet. Adenosine triphosphate (ATP) delivered via membrane, phosphorylated biotinylated captured streptavidin affinity...
The pharmaceutical industry has been continually challenged by dwindling target diversity. To obviate this trend, phenotypic screens have adopted, complementing target-centric screening approaches. Phenotypic identify drug leads using clinically relevant and translatable mechanisms, remaining agnostic to targets. While anonymity is advantageous early in the discovery process, it poses challenges hit progression, including development of backup series, retaining desired pharmacology during...
The catalytic activity of methionine aminopeptidase-2 (MetAP2) has been pharmacologically linked to cell growth, angiogenesis, and tumor progression, making this an attractive target for cancer therapy. An assay monitoring specific protein changes in response MetAP2 inhibition, allowing pharmacokinetic (PK)/pharmacodynamic (PD) models be established, could dramatically improve clinical decision-making. Candidate MetAP2-specific substrates were discovered from undigested culture-derived...