A5019210873- Monoclonal and Polyclonal Antibodies Research
- CAR-T cell therapy research
- Organometallic Complex Synthesis and Catalysis
- Immune Cell Function and Interaction
- Peptidase Inhibition and Analysis
- Nanoparticle-Based Drug Delivery
- Cytokine Signaling Pathways and Interactions
- Cancer Research and Treatments
- Metal complexes synthesis and properties
- Synthesis and Biological Evaluation
- Immune Response and Inflammation
- Crystal structures of chemical compounds
- Hormonal Regulation and Hypertension
- NF-κB Signaling Pathways
- X-ray Diffraction in Crystallography
- Synthesis and characterization of novel inorganic/organometallic compounds
- Adenosine and Purinergic Signaling
- Synthesis and Reactivity of Heterocycles
- Fluorine in Organic Chemistry
- Immunotherapy and Immune Responses
- Coordination Chemistry and Organometallics
- Synthesis and biological activity
- Magnetism in coordination complexes
- Peroxisome Proliferator-Activated Receptors
- Synthesis and Characterization of Heterocyclic Compounds
Amgen (United States)
2005-2015
BASF (United States)
1987-2015
BASF (Germany)
1990-2015
Clausthal University of Technology
2015
Pfizer (United States)
2004
Abbott (Germany)
2003
Robert Bosch (Germany)
1990-2002
Universidad Complutense de Madrid
1990
MRC Laboratory of Molecular Biology
1990
University of Oxford
1990
Absorption effects usually present the most serious source of systematic error in determination structure factors from single-crystal X-ray diffraction measurements if crystal is not ground to a sphere or cylinder. A novel method proposed for correction these data collected on diffractometer. The works premise that manifestation errors due absorption, unlike other sources error, will be evenly distributed through reciprocal space, but localized. Fourier series polar angles incident and...
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL cholesterol (LDL-C) by interacting with the receptor (LDLR) and is an attractive therapeutic target for LDL-C lowering. We have generated a neutralizing anti-PCSK9 antibody, mAb1, that binds to epitope on PCSK9 adjacent region required LDLR interaction. In vitro, mAb1 inhibits binding attenuates PCSK9-mediated reduction in protein levels, thereby increasing uptake. A combination of statin increases levels HepG2 cells...
The eukaryotic initiation factor 4E (eIF4E) plays a central role in the of gene translation and subsequent protein synthesis by binding 5' terminal mRNA cap structure. We designed synthesized series novel compounds that display potent affinity against eIF4E despite their lack ribose moiety, phosphate, positive charge as present m7-GMP. biochemical activity compound 33 is 95 nM for an SPA assay. More importantly, has IC(50) 2.5 μM inhibiting cap-dependent rabbit reticular cell extract assay...
Hepsin is a membrane-anchored, trypsin-like serine protease with prominent expression in the human liver and tumours of prostate ovaries. To better understand biological functions hepsin, we identified macromolecular substrates employing tetrapeptide PS-SCL (positional scanning-synthetic combinatorial library) screen that rapidly determines P1–P4 substrate specificity. exhibited strong preference at P1 position for arginine over lysine, favoured threonine, leucine or asparagine P2, glutamine...
Novel non-nucleoside inhibitors of the HCV RNA polymerase (NS5b) with sub-micromolar biochemical potency have been identified which are selective for inhibition NS5b over other polymerases. The structures complexes formed between several these and were determined by X-ray crystallography, found to bind in an allosteric binding site separate from active site. Structure−activity relationships structural studies mechanism action compounds this series, possess drug-like properties, as unique,...
JAK (Janus family of cytoplasmic tyrosine kinases) kinase 2 (TYK2) participates in signaling through cytokine receptors involved immune responses and inflammation. JAKs are characterized by dual domain: a domain (JH1) that is preceded pseudokinase (JH2). The majority disease-associated mutations map to JH2, demonstrating its central regulatory function. JH2s were considered catalytically inactive, but JAK2 JH2 was found have low autoregulatory catalytic activity. Whether the other share ATP...
Extracellular adenosine (ADO), present in high concentrations the tumor microenvironment (TME), suppresses immune function via inhibition of T cell and NK activation. Intratumoral generation ADO depends on sequential catabolism ATP by two ecto-nucleotidases, CD39 (ATP → AMP) CD73 (AMP ADO). Inhibition eliminates a major pathway production TME can reverse ADO-mediated suppression. Extensive interrogation structure–activity relationships (SARs), structure-based drug design, optimization...
A novel class of endothelin-A receptor ligands was discovered by high-throughput screening. Lead structure optimization led to highly potent antagonists which can be synthesized in a short sequence. The compounds are endothelin-A-selective, orally available, and show long duration action.
Retinol-binding protein 4 (RBP4) transports retinol from the liver to extrahepatic tissues, and RBP4 lowering is reported improve insulin sensitivity in mice. We have identified A1120, a high affinity (K(i) = 8.3 nm) non-retinoid ligand for RBP4, which disrupts interaction between its binding partner transthyretin. Analysis of RBP4-A1120 co-crystal structure reveals that A1120 induces critical conformational changes at RBP4-transthyretin interface. Administration mice lowers serum levels...
We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, SAR analysis, using cell-based assays, led to discovery 28 (AMG 925), potent orally bioavailable inhibitor CDK4 FLT3, including many mutants reported date. Compound inhibits proliferation panel human tumor cell lines Colo205 (Rb(+)) U937 (FLT3(WT)) induced death in MOLM13 (FLT3(ITD)) even...
Sphingosine kinases (SPHKs) are enzymes that phosphorylate the lipid sphingosine, leading to formation of sphingosine-1-phosphate (S1P). In addition well established role extracellular S1P as a mitogen and potent chemoattractant, SPHK activity has been postulated be an important intracellular regulator apoptosis. According proposed rheostat theory, shifts balance from pro-apoptotic sphingolipids ceramide sphingosine mitogenic S1P, thereby determining susceptibility cell apoptotic stress....