A5075317270- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Crystallography and molecular interactions
- Chemical Synthesis and Analysis
- Carbohydrate Chemistry and Synthesis
- Cancer-related Molecular Pathways
- Glycosylation and Glycoproteins Research
- Cholesterol and Lipid Metabolism
- PI3K/AKT/mTOR signaling in cancer
- Peptidase Inhibition and Analysis
- Cancer Genomics and Diagnostics
- Click Chemistry and Applications
- Epigenetics and DNA Methylation
- Sphingolipid Metabolism and Signaling
- HIV/AIDS drug development and treatment
- Chronic Lymphocytic Leukemia Research
- Monoclonal and Polyclonal Antibodies Research
- Immune Cell Function and Interaction
- Synthesis of Indole Derivatives
- Protease and Inhibitor Mechanisms
- Analytical Chemistry and Chromatography
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- RNA modifications and cancer
- Lymphoma Diagnosis and Treatment
- Microtubule and mitosis dynamics
Novartis (Switzerland)
2003-2020
Novartis Institutes for BioMedical Research
2011-2020
Institute Cancer De La Loire Lucien Neuwirth
2017
Genomics Institute of the Novartis Research Foundation
2015
ETH Zurich
2003-2011
Swiss National Science Foundation
2003-2011
Université de Haute-Alsace
2001-2003
Ingenierie des Materiaux polymeres
1999
As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as clinical candidate is currently phase 1 development. This article provides overview discovery this new inhibitor. The following aspects are addressed: mechanism action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic pharmacodynamic properties,...
Bruton's tyrosine kinase (BTK), a cytoplasmic kinase, plays central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors limited to oncology indications based on their suboptimal selectivity. We describe the discovery preclinical profile LOU064 (remibrutinib, 25), potent, highly selective inhibitor. exhibits exquisite selectivity due binding inactive conformation has potential best-in-class inhibitor...
Abstract One of the benefits β‐peptides as potential candidates for biological applications is their stability against common peptidases. Attempts have been made to rationalize this by altering electron availability a given amide carbonyl bond through introduction polar substituents at α‐position single β ‐amino acid. Such β‐amino acids (β‐homoglycine, β‐homoalanine), containing one or two fluorine atoms hydroxy group in α‐position, were prepared enantiopure form. A versatile method...
Biomarkers for patient selection are essential the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report discovery a novel strategy p53–HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, have identified gene expression signature consisting 13 up-regulated genes that predicts to NVP-CGM097 both lines patient-derived tumor xenograft models....
The G protein‐coupled receptor EBI2 (Epstein–Barr virus‐induced gene 2) is activated by 7 α , 25‐dihydroxycholesterol (7 25HC) and plays a role in T cell‐dependant antibody response B cell migration. Aberrant signaling implicated range of autoimmune disorders however its the CNS remains unknown. Here we characterize functional GLIA cells using primary human astrocytes knockout animals. We find mouse express enzymes necessary for synthesis degradation 25HC. In astrocytes, activation...
Deregulated kinase activities of tropomyosin receptor (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety cancer types. In particular, several chromosomal rearrangements involving TRKA reported colorectal, papillary thyroid, glioblastoma, melanoma, lung tissue that are believed the key oncogenic driver these tumors. By screening Novartis compound collection, novel imidazopyridazine TRK inhibitor was identified served as launching point for...
Oxysterols have recently been identified as natural ligands for a G protein-coupled receptor called EBI2 (aka GPR183) ( Nature 2011 , 475 524 ; 519 ). is highly expressed in immune cells J. Biol. Chem. 2006 281 13199 ), and its activation has shown to be critical the adaptive response genetically linked autoimmune diseases such type I diabetes 2010 467 460 Here we describe isolation of potent small molecule antagonist receptor. First, agonist NIBR51 (1), which enabled identification...
The β-heptapeptides H-βhVal-βhAla-βhLeu-βhAla(Xn)-βhVal-βhAla-βhLeu-OH 3–7 with central 3-amino-2-fluoro-, 3-amino-2,2-difluoro-, or 3-amino-2-hydroxybutanoic acid residues (βhAla(Xn)) of like and unlike configuration were subjected to a detailed NMR analysis in MeOH solution. For the geminal difluoro for F- OH-substituted derivatives u-configuration (see 5, 4, 7, resp.), 14-helices found, i.e., axial disposition hetero atoms on helix. two compounds containing l-configured β-amino moieties 3...
Abstract Multigram amounts of suitably protected β 2 ‐amino acids with 17 the 20 proteinogenic side chains are prepared by diastereoselective reactions Li, B, or Ti enolates corresponding 3‐acyl‐4‐isopropyl‐5,5‐diphenyloxazolidin‐2‐ones (acyl‐DIOZ; 1 ) appropriate electrophiles (amidomethylation, hydroxyalkylation, (benzyloxycarbonyl)methylation) in yields 55–90% and diastereoselectivities 80 to >97% ( Scheme ). The primary products – 8 thus obtained converted standard procedures Table...
Abstract The preparation of (2 S ,3 )‐ and R )‐2‐fluoro (3 )‐2,2‐difluoro‐3‐amino carboxylic acid derivatives, 1 – 3 , from alanine, valine, leucine, threonine, β h‐alanine ( Schemes 2, Table ) is described. stereochemical course (diethylamino)sulfur trifluoride (DAST) reactions with N ‐dibenzyl‐2‐amino‐3‐hydroxy 3‐amino‐2‐hydroxy esters discussed Fig. ). fluoro‐ ‐amino residues have been incorporated into pyrimidinones 11 13 ; 2 cyclic ‐tri‐ ‐tetrapeptides 17 19 21 23 Scheme rigid...
Hdm2 (human MDM2, human double minute 2 homologue) counteracts p53 function by direct binding to and ubiquitin-dependent protein degradation. Activation of inhibitors the p53-Hdm2 interaction is being pursued as a therapeutic strategy in wild-type cancers. In addition, HdmX MDMX, MDM4) was also identified an important target efficiently reactivate p53, it likely that dual inhibition beneficial. Herein we report four new X-ray structures for five complexes, involving different classes...
Abstract Cytokine-primed neutrophils can undergo a nonapoptotic type of cell death using components the necroptotic pathway, including receptor-interacting protein kinase-3 (RIPK3), mixed lineage kinase-like (MLKL) and NADPH oxidase. In this report, we provide evidence for potential role serine proteases in CD44-mediated GM-CSF–primed human neutrophils. Specifically, observed that several inhibitors known to block enzymatic function fibroblast activation protein-α (FAP-α) were able reactive...
Abstract β ‐Amino acids 1 – 3 with OH and F substituents in the α ‐position have been prepared ( Scheme ) from natural S )‐ ‐amino alanine, valine, leucine, incorporated into ‐hexa‐ ‐heptapeptides 4 12 . The peptide syntheses were performed according to a conventional solution strategy (Boc/Bn protection) fragment coupling. new ‐peptides (series without b terminal protection isolated HPLC‐pure form characterized by NMR spectroscopy MALDI mass spectrometry. chemical properties as well...
Bruton's tyrosine kinase (BTK) is a member of the TEC family and selectively expressed in subset immune cells. It key regulator antigen receptor signaling B cells Fc mast macrophages. A BTK inhibitor will likely have positive impact on autoimmune diseases which are caused by autoreactive immune-complex driven inflammation. We report design, optimization, characterization potent selective covalent inhibitors. Starting from reversible 3 binding to an inactive conformation BTK, we designed...
The title compounds were prepared from valine-derived N-acylated oxazolidin-2-ones, 1–3, 7, 9, by highly diastereoselective (≥ 90%) Mannich reaction (→ 4–6; Scheme 1) or aldol addition 8 and 10; 2) of the corresponding Ti- B-enolates as key step. superiority ‘5,5-diphenyl-4-isopropyl-1,3-oxazolidin-2-one’ (DIOZ) was demonstrated, once more, in these reactions subsequent transformations leading to various t-Bu-, Boc-, Fmoc-, Cbz-protected β2-homoamino acid derivatives 11–23 (Schemes 3–6). use...
Abstract An effective strategy to restore p53 activity in cancer cells containing wild type is inhibit the Mdm2-p53 protein-protein interaction (PPI). NVP-CGM097 a novel PPI inhibitor under evaluation Phase I clinical trial. It binds binding-site of Mdm2 protein, disrupting between both proteins, leading an activation pathway. The main biophysical and biochemical inhibitory characteristics are presented here. These include affinity constant for nanomolar range selectivity 3 orders magnitude...
The syntheses of all four imidazolo-piperidino-pentoses in the L-series ent-2 to ent-5, and three out possible stereomers D-series 3, 4, 5, are reported. linear imidazolo sugar precursors were prepared, either by double condensation formamidine with protected aldohexoses, or nucleophilic addition a lithiated imidazole derivative aldotetroses. Cyclisation these imidazolo-carbohydrates was performed intramolecular SN2 reactions. These followed deprotection target molecules. pairs opposite...
Abstract Assuming the transition state of glycosyltransferase inhibitors to be similar those encountered with potent glycosidase − i.e. a flattened conformation positively charged anomeric centre we worked out synthesis D ‐ arabino ‐configured phosphonic acid target molecule 2 derived from an imidazolo‐sugar. The key synthetic intermediate is linear imidazolo L xylo compound 10 which could obtained, either threo precursor 6 by coupling reaction imidazole derivative 5 , or ‐sorbose. A...
The syntheses of the four imidazolo-piperidino-pentoses 3−6, which belong to D-series, and their L-enantiomers, ent-3 ent-6, are reported. Ascorbic acid isoascorbic were converted over several steps into L-threo/L-erythro- D-erythro/D-threo-configured aldotetroses, respectively, key building blocks for eight target imidazolo-pentoses cited above. Nucleophilic addition a metallated imidazole any one these aldotetroses gave corresponding two diastereomeric adducts, intramolecular cyclisation...