A5066499315- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Asthma and respiratory diseases
- Cell death mechanisms and regulation
- Chemical Reaction Mechanisms
- Food Allergy and Anaphylaxis Research
- Allergic Rhinitis and Sensitization
- Metal complexes synthesis and properties
- Chemical Synthesis and Analysis
- Organic Chemistry Cycloaddition Reactions
- Asymmetric Synthesis and Catalysis
- CRISPR and Genetic Engineering
- Cancer-related Molecular Pathways
- Click Chemistry and Applications
- Inorganic and Organometallic Chemistry
- PARP inhibition in cancer therapy
- Hemoglobin structure and function
- Chemical synthesis and alkaloids
- Chemical Synthesis and Reactions
- Asymmetric Hydrogenation and Catalysis
- Neuroscience and Neural Engineering
- Computational Drug Discovery Methods
- Wnt/β-catenin signaling in development and cancer
- Fluorine in Organic Chemistry
- Insect Resistance and Genetics
University of Cambridge
2024
Medical Research Council
2024
Domainex (United Kingdom)
2011-2022
Microbiology Institute of Shaanxi
2018
Institute of Microbiology
2018
Chinese Academy of Sciences
2018
St George's, University of London
2018
Innovative Vector Control Consortium
2016
Liverpool School of Tropical Medicine
2016
Horizon Discovery (United Kingdom)
2007
Heart disease is a paramount cause of global death and disability. Although cardiomyocyte plays causal role its suppression would be logical, no clinical counter-measures target the responsible intracellular pathways. Therapeutic progress has been hampered by lack preclinical human validation. Mitogen-activated protein kinase kinase-4 (MAP4K4) activated in failing hearts relevant rodent models. Using induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) MAP4K4 gene silencing, we...
BRCA2 controls RAD51 recombinase during homologous DNA recombination (HDR) through eight evolutionarily conserved BRC repeats, which individually engage via the motif Phe-x-x-Ala. Using structure-guided molecular design, templated on a monomeric thermostable chimera between human and archaeal RadA, we identify CAM833, 529 Da orthosteric inhibitor of RAD51:BRC with Kd 366 nM. The quinoline CAM833 occupies hotspot, Phe-binding pocket methyl substituted α-methylbenzyl group Ala-binding pocket....
Reducing glucocorticoid exposure in the brain via intracellular inhibition of cortisol-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has emerged as a therapeutic strategy to treat cognitive impairment early Alzheimer's disease (AD). We sought discover novel, brain-penetrant 11β-HSD1 inhibitors potential medicines for treatment AD.Medicinal chemistry optimization series amido-thiophene analogues was performed identify potent and selective with optimized oral...
A new group of CO-releasing molecules, CO-RMs, based on cyclopentadienyl iron carbonyls have been identified. X-Ray structures determined for [(η-C5H4CO2Me)Fe(CO)2X], X = Cl, Br, I, NO3, CO2Me, [(η-C5H4CO2Me)Fe(CO)2]2, [(η-C5H4CO2CH2CH2OH)Fe(CO)2]2 and [(η-C5H4CO2Me)Fe(CO)3][FeCl4]. Half-lives CO release, 1H, 13C, 17OC NMR IR spectra along with some biological data these compounds, [(η-C5H4CO2CH2CH2OH)Fe(CO)3]+ [{η-C5H4(CH2)nCO2Me}Fe(CO)3]+, n 1, 2. More specifically, cytotoxicity assays...
Aurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization enzymatic activity of are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery develop small molecule inhibitors A-TPX2 protein-protein (PPI). Our compound,
Bacterial sortases are transpeptidases that covalently anchor surface proteins to the peptidoglycan of Gram-positive cell wall. Sortase protein anchoring is mediated by a conserved wall sorting signal on anchored protein, comprising C-terminal recognition sequence containing an "LPXTG-like" motif, followed hydrophobic domain and positively charged tail.We report Clostridium difficile strain 630 encodes single sortase (SrtB). A FRET-based assay was used confirm recombinant SrtB catalyzes...
Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 house dust mites (HDM) are meaningful targets in this quest because they globally prevalent and clinically important triggers asthma. HDM cysteine peptidases whose proteolytic activity essential steps allergy cascade. Using allergen Der p an archetype structure-based drug discovery, we have identified series novel, reversible...
Given the poor track record to date of animal models for creating cardioprotective drugs, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been proposed as a therapeutically relevant platform guide target validation and cardiac drug development. Mitogen-Activated Protein Kinase Kinase-4 (MAP4K4) is an "upstream" member MAPK superfamily that implicated in muscle cell death from oxidative stress, based on gene silencing pharmacological inhibition hPSC-CMs. A further role...
A study of the regioselectivity enolate nucleophile addition to tricarbonyl(dienylium)iron complexes with structure (1) is reported. It has been found that better selectivity for 1-substituted dienylium terminus achieved using 4-isopropoxy-substituents than 4-methoxy-substituents. The nature countercation also affect significantly its addition, and these results are discussed in terms factors which likely control reaction.
Abstract Reducing infarct size (IS) by interfering with mechanisms for cardiomyocyte death remains an elusive goal. DMX-5804, a selective inhibitor of the stress-activated kinase MAP4K4, suppresses cell in mouse myocardial infarction (MI), human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), and 3D engineered heart tissue, whose fidelity to biology is hoped strengthen route clinical success. Here, DMX-10001, soluble, rapidly cleaved pro-drug was developed i.v. testing large-mammal...
δ-Alkynyl oximes undergo a concerted 2n + 2π+ 2σ 1,3-azaprotio cyclotransfer (APT) reactiongenerating cyclic N-vinyl nitrones which have been trapped in cycloaddition reactions; MNDO and AM1 calculations transition-state modelling provide support for the observed greater facility of oxime–alkyne reactions compared to oxime–alkene reactions.
Group 1 allergens of house dust mites (HDM) are globally significant triggers allergic disease. They considered as initiator because their protease activity enables the development allergy to a spectrum unrelated from various sources. This initiator-perpetuator function identifies HDM attractive drug design targets for first small-molecule approach directed towards non-human, root cause trigger The purpose this study was to: (i) identify exemplar inhibitors these using Der p template, and...
The tankyrase proteins (TNKS, TNKS2) are attractive anti-cancer drug targets, particularly as inhibition of their catalytic activity has been shown to antagonise oncogenic WNT signalling.
Phenylselenyl bromide-induced cyclisation of γ- and δ-unsaturated aldoxime ketoxime O-allyl O-benzyl ethers is followed by a slow fragmentation furnishing cyclic imines which are readily reduced to pyrrolidines, piperidines or tetrahydroisoquinolines sodium borohydride; dialkenyl oximes yield quinolizidines an analogous sequence terminating in mercury(II)-induced cyclisation.
Abstract The IKK‐related kinases, IKKε and TBK1, have essential roles in innate immunity part through modifying MYD88 signalling from the Toll‐like receptors to regulate NF‐κB signalling. We investigated expression function of diffuse large B‐cell lymphoma (DLBCL). DLBCL cell lines patient‐derived xenografts were used determine their sensitivity TBK1 inhibitors. To understand secreted factors determined following administration Gene microarrays transcriptional effects Higher mRNA levels...