A5077799085- Adenosine and Purinergic Signaling
- Antiplatelet Therapy and Cardiovascular Diseases
- Synthesis of β-Lactam Compounds
- Monoclonal and Polyclonal Antibodies Research
- Receptor Mechanisms and Signaling
- T-cell and B-cell Immunology
- Growth Hormone and Insulin-like Growth Factors
- Pharmacological Receptor Mechanisms and Effects
- Neuroendocrine Tumor Research Advances
- Platelet Disorders and Treatments
- CAR-T cell therapy research
- Complement system in diseases
- Ion channel regulation and function
- HER2/EGFR in Cancer Research
- Pancreatic function and diabetes
- Renal Transplantation Outcomes and Treatments
- Cardiac electrophysiology and arrhythmias
- Central Venous Catheters and Hemodialysis
- Parkinson's Disease Mechanisms and Treatments
- Lipoproteins and Cardiovascular Health
- Animal Genetics and Reproduction
- Oxidative Organic Chemistry Reactions
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- interferon and immune responses
- Ion Channels and Receptors
Quantitative BioSciences
2020-2025
Merck & Co., Inc., Rahway, NJ, USA (United States)
2025
United States Military Academy
2023
Bristol-Myers Squibb (United States)
2012-2017
Bristol-Myers Squibb (Germany)
2013-2014
London Health Sciences Centre
1999
Royal College of Emergency Medicine
1999
University of Missouri
1999
Texas A&M University
1999
Torrey Pines Institute For Molecular Studies
1998
Pharmacological activation of the STING (stimulator interferon genes)-controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report identification MSA-2, an orally available non-nucleotide human agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated stimulated interferon-β secretion in tumors, induced regression with durable antitumor immunity, synergized anti-PD-1 therapy. Experimental theoretical analyses showed...
A K + channel gene has been cloned from Drosophila melanogaster by complementation in Saccharomyces cerevisiae cells defective for uptake. Naturally expressed the neuromuscular tissues of adult flies, this confers transport capacity on yeast when heterologously expressed. In Xenopus laevis oocytes, expression yields an ungated -selective current whose attributes resemble “leak” conductance thought to mediate resting potential vertebrate myelinated neurons but molecular nature long remained...
The study of the five somatostatin receptor subtypes (SSTx, where x is subtype number) has been hampered by lack high affinity antagonists. Potent and selective antagonists would increase our understanding SST structure, function, regulation. In this study, identification novel disulfide-linked cyclic octapeptide described. contain a core structure DL-cysteine pair at positions 2 7 peptides. Substitution D-cysteine position with an L-cysteine converts full antagonist into agonist. All are...
A detailed analysis of structural and functional aspects G-protein-coupled receptors, as well discovery novel pharmacophores that exert their effects on members this class will be facilitated by development a yeast-based bioassay. To end, yeast strains functionally express the rat somatostatin receptor subtype 2 (SSTR2) were constructed. High-affinity binding sites for ([125I-Tyr-11]S-14) comparable to those in native tissues detected membrane extracts at levels equivalent alpha-mating...
The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps most effective experimental models is use reagents to block CD40/CD154 pathway. Unfortunately, successful clinical translation anti-CD154 has not been achieved. In an attempt develop agent that as previous CD154 blocking antibodies but lacks risk thromboembolism, we evaluated efficacy and safety a novel anti-human domain antibody (dAb, BMS-986004). dAb...
CD40-CD40L interactions play a critical role in regulating immune responses. Blockade of CD40L by Abs, such as the anti-CD40L Ab 5c8, demonstrated positive clinical effects patients with autoimmune diseases; however, incidents thromboembolism (TE) precluded further development these molecules. In this study, we examined Fc domain interaction FcγRs modulating platelet activation and potential for TE. Our results show that 5c8 wild-type IgG1 is responsible activation, measured induction PAC-1...
Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents may offer a safety advantage over P2Y12 in terms of reduced liabilities. In this article, we describe the structural modification tert-butyl phenoxy portion lead compound 1 subsequent discovery novel series conformationally constrained ortho-anilino diaryl ureas. particular, spiropiperidine indoline-substituted ureas described potent, orally bioavailable...
Two distinct G protein-coupled purinergic receptors, P2Y1 and P2Y12, mediate ADP-driven platelet activation. The clinical effectiveness of P2Y12 blockade is well established. Recent preclinical data suggest that inhibition provide equivalent antithrombotic efficacy, while targeting has the potential for reduced bleeding liability. In this account, discovery a 2-(phenoxypyridine)-3-phenylurea chemotype inhibited ADP-mediated aggregation in human blood samples described. Optimization series...
Adenosine diphosphate (ADP)-mediated platelet aggregation is signaled through two distinct G protein-coupled receptors (GPCR) on the surface: P2Y12 and P2Y1. Blocking receptor a clinically well-validated strategy for antithrombotic therapy. P2Y1 antagonists have been shown to potential provide equivalent efficacy as inhibitors with reduced bleeding in preclinical animal models. We previously reported discovery of potent orally bioavailable antagonist, 1. This paper describes further...
Intracellular accumulation of aberrantly phosphorylated aggregated tau protein can contribute to neuronal dysfunction associated with many neurodegenerative diseases. Thus, removing such species is an attractive therapeutic hypothesis for these Targeted degradation (TPD) strategies leveraging the autophagy-lysosome pathway (ALP) are promising approaches decrease aggregates by designating them degradation. Here, we developed a novel heterobifunctional molecule, MRL828, combining...
AbstractAbstractGrowth hormone releasing (GHRH) is the positive regulator of growth synthesis and secretion in anterior pituitary. The peptide confers activity by binding to a seven transmembrane domain G protein-coupled receptor. Signal transduction proceeds through subsequent Gas stimulation adenylyl cyclase. To investigate ligand/receptor receptor/G protein associations, human GHRH receptor was expressed modified S. cerevisiae strain which allows for facile measurement cell prototrophy...
The rat A2a adenosine receptor, a G protein-coupled was functionally expressed in the yeast Saccharomyces cerevisiae. High affinity binding sites for agonists were detected membranes containing endogenous Grx protein Gpa1. Agonist saturation isotherms using [3H]5'-N-ethylcarboxamidoadenosine indicated that receptor cell displays pharmacological properties equivalent to those observed when is human embryonic kidney 293 membranes. rank order of potency various competition assays performed with...
We determined the dose response of ADP antagonist clopidogrel (0.3-50 mg/kg p.o.) in rat models thrombosis and provoked bleeding correlated these activities to ex vivo platelet activation. Carotid artery was induced by FeCl<sub>2</sub>. Bleeding time measured mesenteric vessel puncture renal cortex or cuticle incision. Platelet biomarkers included standard ADP-induced aggregation, P2Y<sub>12</sub> receptor occupancy, phosphorylation vasodilator-stimulated phosphoprotein. Clopidogrel...
Somatostatin (SRIF) is the main inhibitory peptide regulating growth hormone (GH) secretion. It has been difficult to establish role of endogenous SRIF release in absence pure antagonists. Although several antagonists have recently described, none shown possess <i>in vivo</i> activity added SRIF. Here, an antagonist with no detectable agonist identified from a synthetic combinatorial hexapeptide library containing 6.4 × 10<sup>7</sup> unique peptides. Each amino-terminally acetylated and...
Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra. Loss-of-function mutations GBA, gene that encodes for lysosomal enzyme glucosylcerebrosidase, are a major genetic risk factor development potentially through accumulation glucosylceramide and glucosylsphingosine CNS. A therapeutic strategy to reduce glycosphingolipid CNS would entail inhibition responsible their synthesis, synthase (GCS)....
Abstract Current antithrombotic discovery efforts target compounds that are highly efficacious in thrombus reduction with less bleeding liability than the standard of care. Preclinical data suggest P2Y 1 antagonists may have lower liabilities 12 while providing similar efficacy. This article describes our continuous SAR a series 7‐hydroxyindolinyl diaryl ureas. When dosed orally, 4‐trifluoromethyl‐7‐hydroxy‐3,3‐dimethylindolinyl analogue 4 was model arterial thrombosis rats limited bleeding....
CD40:CD40L interactions play a critical role in regulating immune responses and offer potential for targeted prevention of transplant rejection. Herein we describe the identification biological properties potent domain antibodies (dAbs) targeting human murine CD40L molecules. Initial screens identified monomeric dAbs against CD40L, which were then formatted as bivalent Fc proteins. In vitro primary cell-based assays leads further optimized to generate molecules that exhibited favorable...