A5052596660- Pharmacogenetics and Drug Metabolism
- Protein Degradation and Inhibitors
- Neural dynamics and brain function
- Neuroscience and Neuropharmacology Research
- Ubiquitin and proteasome pathways
- Metabolomics and Mass Spectrometry Studies
- Multiple Myeloma Research and Treatments
- Drug-Induced Hepatotoxicity and Protection
- Phytochemistry and Biological Activities
- Liver Disease Diagnosis and Treatment
- Vestibular and auditory disorders
- Analytical Chemistry and Chromatography
- Microplastics and Plastic Pollution
- Pharmacological Effects and Toxicity Studies
- Bioactive natural compounds
- Biological Activity of Diterpenoids and Biflavonoids
- Hemoglobinopathies and Related Disorders
- Iron Metabolism and Disorders
- Memory and Neural Mechanisms
- Natural product bioactivities and synthesis
- Antibiotic Resistance in Bacteria
- Photoreceptor and optogenetics research
- Drug Transport and Resistance Mechanisms
- Pesticide Residue Analysis and Safety
- Recycling and Waste Management Techniques
Nankai University
2025
Xiamen University
2021-2024
Shaanxi Normal University
2024
Centre Interdisciplinaire de Recherche en Biologie
2019-2023
Centre National de la Recherche Scientifique
2011-2023
Inserm
2011-2023
Collège de France
2019-2023
Université Paris Sciences et Lettres
2019-2022
Henan University
2022
Tsinghua University
2017-2021
PROTACs-induced targeted protein degradation has emerged as a novel therapeutic strategy in drug development and attracted the favor of academic institutions, large pharmaceutical enterprises (e.g., AstraZeneca, Bayer, Novartis, Amgen, Pfizer, GlaxoSmithKline, Merck, Boehringer Ingelheim, etc.), biotechnology companies. PROTACs opened new chapter for development. However, any technology will face many problems challenges. Perspectives on potential opportunities challenges contribute to...
A focused PROTAC library hijacking cancer therapeutic target CDK6 was developed. design principle as "match/mismatch" proposed for understanding the degradation profile differences in these PROTACs. Notably, potent PROTACs with specific and remarkable potential were generated by linking inhibitor palbociclib E3 ligase CRBN recruiter pomalidomide. The strongly inhibited proliferation of hematopoietic cells including multiple myeloma robustly degraded copy-amplified/mutated forms CDK6,...
Highly synchronous neuronal assembly activity is deemed essential for cognitive brain function. In theory, such synchrony could coordinate multiple areas performing complementary processes. However, cell assemblies have been observed only in single structures, typically cortical areas, and little known about their with downstream subcortical as the striatum. Here, we demonstrate distributed activated at high (∼10 ms) spanning prefrontal cortex addition to including neurons different...
The pharmacokinetic properties of drugs may be altered by kinetic deuterium isotope effects. With specifically deuterated model substrates and metabolized aldehyde oxidase, we demonstrate how knowledge the enzyme9s reaction mechanism, species differences in role played other enzymes a drug9s metabolic clearance, systemic clearance mechanisms are critically important for application Ex vivo methods to project outcome using carbazeran zoniporide with hepatic systems importance establishing...
Focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase, exerts kinase-dependent enzymatic functions and kinase-independent scaffolding functions, both of which are crucial in cancer development, early embryonic reproduction. However, previous efforts for FAK blocking mainly focus on inhibitors. Proteolysis targeting chimeras (PROTACs) heterobifunctional molecules that allow direct post-translational knockdown proteins via ubiquitination target by E3 ubiquitin ligase subsequent...
The BCR–ABL fusion oncoprotein causes chronic myeloid leukemia or acute lymphoblastic in Ph+ patients because the ABL kinase is constitutively activated. However, current clinical treatment with inhibitors seriously limited by drug resistance and adverse effects. Although emerging proteolysis-targeting chimeras (PROTACs) have been introduced to degrade BCR–ABL, most of them showed activity could not overcome common drug-resistant mutants, especially for T315I mutant. Herein, we...
Viral infections are increasing and probably long-lasting global risks. In this study, a chemical library was exploited by phenotypic screening to discover new antiviral inhibitors. After optimizations from hit lead, novel potent small molecule (RYL-634) identified, showing excellent broad-spectrum inhibition activity against various pathogenic viruses, including hepatitis C virus, dengue Zika chikungunya enterovirus 71, human immunodeficiency respiratory syncytial others. The mechanism of...
Telaprevir 2 (VX-950), an inhibitor of the hepatitis C virus (HCVa) NS3-4A protease, is in phase 3 clinical trials. One major metabolites its P1-(R)-diastereoisomer, (VRT-394), containing inversion at chiral center next to α-ketoamide on exchange a proton with solvent. Compound approximately 30-fold less active against HCV protease. In attempt suppress epimerization without losing activity that site was replaced deuterium (d). The compound 1 (d-telaprevir) as efficacious vitro inhibition...
Recent regulatory guidance suggests that metabolites identified in human plasma should be present at equal or greater levels one of the animal species used safety assessments. In this report, a high-performance liquid chromatography-tandem mass spectrometry method is described whereby quantitative comparisons exposures to between can obtained absence authentic standards metabolites, calibration curves, and other attributes standard bioanalytical methods. This novel was tested using six...
3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an eight-pass transmembrane protein in the endoplasmic reticulum (ER) and a classical drug target to treat dyslipidemia. Statins including well-known atorvastatin (Lipitor; Pfizer) have been widely used for prevention treatment of cardiovascular disease decades. However, statins can elicit compensatory upregulation HMGCR cause adverse effects skeletal muscle damage. They are ineffective patients with statin intolerance. Inspired by...
To investigate the hepatoprotective effect of a Cichorium intybus L. extract (CIE) on CCl4-induced hepatic fibrosis in rats.
The nucleusLocus Coeruleus (LC) is the major source of forebrain norepinephrine. LC implicated in arousal, response to novelty, and cognitive functions, including decision-making behavioral flexibility. One hypothesis that activation promotes rapid shifts cortical attentional networks following changes environmental contingencies. Recent recordings further suggest critical for mobilizing resources deal with challenging situations. In present study optogenetically identified neuronal activity...
Teixobactin, targeting lipid II, represents a new class of antibiotics with novel structures and has excellent activity against Gram-positive pathogens. We developed convergent method to synthesize series teixobactin analogues explored structure–activity relationships. obtained equipotent simplified analogues, replacing the l-allo-enduracididine lysine, substituting oxygen nitrogen on threonine, adding phenyl group d-phenylalanine. On basis antibacterial activities that resulted from...
Teixobactin represents a new class of antibiotics with novel structure and excellent activity against Gram-positive pathogens Mycobacterium tuberculosis. Herein, we report one-pot reaction to conveniently construct the key building block L-allo-Enduracidine in 30-gram scale just one hour convergent strategy (3 + 2 6) accomplish gram-scale total synthesis teixobactin. Several analogs are described, 20 26 identified as most efficacious 3~8-fold 2~4-fold greater potency vancomycin resistant...
Recent regulatory guidance suggests that drug metabolites identified in human plasma should be present at equal or greater levels least one of the animal species used safety assessments (MIST). Often synthetic standards for do not exist, thus this has introduced multiple challenges regarding quantitative comparison between and animals. Various bioanalytical approaches are described to evaluate exposure vs. human. A simple LC/MS/MS peak area ratio approach is most facile applicable make a...
In the search for novel bile acid (BA) biomarkers of liver organic anion-transporting polypeptides (OATPs), cynomolgus monkeys received oral rifampicin (RIF) at four dose levels (1, 3, 10, and 30 mg/kg) that generated plasma-free <i>C</i><sub>max</sub> values (0.06, 0.66, 2.57, 7.79 <i>µ</i>M, respectively) spanning reported in vitro IC<sub>50</sub> OATP1B1 OATP1B3 (≤1.7 <i>μ</i>M). As expected, area under plasma concentration-time curve (AUC) an OATP probe drug (i.v....
Rapid information on metabolic profiling is required to evaluate the structural liabilities of drug candidates in early discovery. In this study, a sensitive and rapid semi-quantitative method was developed simultaneously monitor candidate metabolites as well collect tandem mass (MS/MS) spectra for subsequent metabolite identification. The simultaneous semi-quantitation identification fresh hepatocytes achieved using high-performance liquid chromatography (HPLC) coupled with hybrid...