A5033979043- Magnolia and Illicium research
- Oxidative Organic Chemistry Reactions
- 14-3-3 protein interactions
- Neuroscience and Neuropharmacology Research
- Biochemical and Molecular Research
- HIV/AIDS drug development and treatment
- Ion channel regulation and function
- Ubiquitin and proteasome pathways
- Molecular Sensors and Ion Detection
- Monoclonal and Polyclonal Antibodies Research
- Cytomegalovirus and herpesvirus research
- Bioactive Compounds and Antitumor Agents
- Viral-associated cancers and disorders
- Herpesvirus Infections and Treatments
- Pharmacological Receptor Mechanisms and Effects
- X-ray Diffraction in Crystallography
- Probiotics and Fermented Foods
- Multiple Myeloma Research and Treatments
- Receptor Mechanisms and Signaling
- Photoreceptor and optogenetics research
- Gut microbiota and health
- Biosimilars and Bioanalytical Methods
- Antimicrobial Peptides and Activities
- Microbial Natural Products and Biosynthesis
- Memory and Neural Mechanisms
Amgen (United States)
2022-2024
Emory University
2009-2023
University of California, San Francisco
2014-2017
PROteolysis TArgeting Chimeras (PROTACs) are hetero-bifunctional small molecules that can simultaneously recruit target proteins and E3 ligases to form a ternary complex, promoting protein ubiquitination degradation via the Ubiquitin-Proteasome System (UPS). PROTACs have gained increasing attention in recent years due certain advantages over traditional therapeutic modalities enabling targeting of previously "undruggable" proteins. To better understand mechanism PROTAC-induced Target Protein...
The compound 4-(5-(4-bromophenyl)-3-(6-methyl-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-4,5-dihydro-1<i>H</i>-pyrazol-1-yl)-4-oxobutanoic acid (DQP-1105) is a representative member of new class <i>N</i>-methyl-d-aspartate (NMDA) receptor antagonists. DQP-1105 inhibited GluN2C- and GluN2D-containing receptors with IC<sub>50</sub> values that were at least 50-fold lower than those for recombinant GluN2A-, GluN2B-, GluA1-, or GluK2-containing receptors. Inhibition was voltage-independent could...
We describe a new class of subunit-selective antagonists N-methyl d-aspartate (NMDA)-selective ionotropic glutamate receptors that contain the (E)-3-phenyl-2-styrylquinazolin-4(3H)-one backbone. The inhibition recombinant NMDA receptor function induced by these quinazolin-4-one derivatives is noncompetitive and voltage-independent, suggesting this family compounds does not exert action on agonist binding site or block channel pore. described here resemble CP-465,022...
N-Methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate that mediate excitatory synaptic transmission and have been implicated in numerous neurological disorders. NMDARs typically comprise two GluN1 GluN2 subunits. The four subtypes (GluN2A-GluN2D) distinct functional properties gene expression patterns, which contribute to diverse roles for the brain. Here, we present a series of GluN2C/2D-selective negative allosteric modulators built around N-aryl benzamide (NAB) core....
Here we describe the synthesis and structure-activity relationship for a class of pyrazoline-containing dihydroquinolone negative allosteric modulators NMDA receptor that show strong subunit selectivity GluN2C- GluN2D-containing receptors over GluN2A- GluN2B-containing receptors. Several members this inhibit responses in nanomolar range are more than 50-fold selective GluN1/GluN2A GluN1/GluN2B receptors, as well AMPA, kainate, GABA, glycine, nicotinic, serotonin, purinergic Analysis purified...
Targeting death receptor-mediated apoptosis has emerged as an effective strategy for cancer therapy. However, certain types of cells are intrinsically resistant to apoptosis. In effort identify agents that can sensitize receptor-induced apoptosis, we have identified honokiol, a natural product with anticancer activity, shown in various preclinical studies, sensitizer Honokiol alone moderately inhibited the growth human lung cells; however, when combined tumor necrosis factor-related...
In vivo clearance mechanisms of therapeutic monoclonal antibodies (mAbs) encompass both target-mediated and target-independent processes. Two distinct determinants overall mAb largely separate influences are non-specific cellular endocytosis subsequent pH-dependent recycling mediated by the neonatal Fc receptor (FcRn), where inter-mAb variability in efficiency processes is observed. Here, we implemented a functional cell-based FcRn assay via Madin-Darby canine kidney type II cells stably...
Targeting of cryptic binding sites represents an attractive but underexplored approach to modulating protein function with small molecules. Using the dimeric protease (Pr) from Kaposi's sarcoma-associated herpesvirus (KSHV) as a model system, we sought dissect putative allosteric network linking site at dimerization interface enzyme function. Five cryogenic X-ray structures were solved monomeric inhibitors bound dimer site. Distinct coordinated movements captured by also revealed alternative...
Abstract Fragment‐based drug discovery has shown promise as an approach for challenging targets such protein–protein interfaces. We developed and applied activity‐based fragment screen against dimeric Kaposi's sarcoma‐associated herpesvirus protease (KSHV Pr) using optimized fluorogenic substrate. Dose–response determination was performed a confirmation screen, NMR spectroscopy used to map inhibitor binding KSHV Pr. Kinetic assays demonstrated that several initial hits also inhibit human...
Subunit-selective inhibition of N-methyl-d-aspartate receptors (NMDARs) is a promising therapeutic strategy for several neurological disorders, including epilepsy, Alzheimer's and Parkinson's disease, depression, acute brain injury. We previously described the dihydroquinoline–pyrazoline (DQP) analogue 2a (DQP-26) as potent NMDAR negative allosteric modulator with selectivity GluN2C/D over GluN2A/B. However, moderate (<100-fold) subunit selectivity, inadequate cell-membrane permeability,...
Supplementary Fig. S3 from The natural product honokiol preferentially inhibits cellular FLICE-inhibitory protein and augments death receptor–induced apoptosis
Supplementary Fig. S3 from The natural product honokiol preferentially inhibits cellular FLICE-inhibitory protein and augments death receptor–induced apoptosis
<div>Abstract<p>Targeting death receptor–mediated apoptosis has emerged as an effective strategy for cancer therapy. However, certain types of cells are intrinsically resistant to apoptosis. In effort identify agents that can sensitize receptor–induced apoptosis, we have identified honokiol, a natural product with anticancer activity, shown in various preclinical studies, sensitizer Honokiol alone moderately inhibited the growth human lung cells; however, when combined tumor...
Supplementary Fig. S1 from The natural product honokiol preferentially inhibits cellular FLICE-inhibitory protein and augments death receptor–induced apoptosis
Supplementary Fig. S2 from The natural product honokiol preferentially inhibits cellular FLICE-inhibitory protein and augments death receptor–induced apoptosis
<div>Abstract<p>Targeting death receptor–mediated apoptosis has emerged as an effective strategy for cancer therapy. However, certain types of cells are intrinsically resistant to apoptosis. In effort identify agents that can sensitize receptor–induced apoptosis, we have identified honokiol, a natural product with anticancer activity, shown in various preclinical studies, sensitizer Honokiol alone moderately inhibited the growth human lung cells; however, when combined tumor...
Supplementary Fig. S1 from The natural product honokiol preferentially inhibits cellular FLICE-inhibitory protein and augments death receptor–induced apoptosis
Supplementary Fig. S2 from The natural product honokiol preferentially inhibits cellular FLICE-inhibitory protein and augments death receptor–induced apoptosis