A5008651904- Chronic Myeloid Leukemia Treatments
- Chronic Lymphocytic Leukemia Research
- Eosinophilic Disorders and Syndromes
- Monoclonal and Polyclonal Antibodies Research
- Quinazolinone synthesis and applications
- Acute Lymphoblastic Leukemia research
- Cytokine Signaling Pathways and Interactions
- Protein Kinase Regulation and GTPase Signaling
- PI3K/AKT/mTOR signaling in cancer
- HER2/EGFR in Cancer Research
- Acute Myeloid Leukemia Research
- Fungal Plant Pathogen Control
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Protein Degradation and Inhibitors
- Immune cells in cancer
- Protein Tyrosine Phosphatases
- Melanoma and MAPK Pathways
- Click Chemistry and Applications
- Histone Deacetylase Inhibitors Research
- Cancer Genomics and Diagnostics
- Epigenetics and DNA Methylation
- Chemical Synthesis and Analysis
- Peptidase Inhibition and Analysis
- Blood disorders and treatments
- Mast cells and histamine
Philipps University of Marburg
2019-2024
New York University
2024
University School
2024
École Polytechnique Fédérale de Lausanne
2012-2021
Medical University of Vienna
2021
CeMM Research Center for Molecular Medicine
2006-2019
Austrian Academy of Sciences
2005-2019
Swiss Group For Clinical Cancer Research
2015-2017
NCCR Chemical Biology - Visualisation and Control of Biological Processes Using Chemistry
2017
Charles Humbert 8
2017
Increasing evidence suggests that the c-Abl protein tyrosine kinase could play a role in pathogenesis of Parkinson's disease (PD) and other neurodegenerative disorders. has been shown to regulate degradation two proteins implicated PD, parkin α-synuclein (α-syn). The inhibition parkin's neuroprotective functions is regulated by c-Abl-mediated phosphorylation parkin. However, molecular mechanisms which activity regulates α-syn toxicity clearance remain unknown. Herein, using NMR spectroscopy,...
Dasatinib is a small-molecule kinase inhibitor used for the treatment of imatinib-resistant chronic myelogenous leukemia (CML). We have analyzed kinases targeted by dasatinib using an unbiased chemical proteomics approach to detect binding proteins directly from lysates CML cells. Besides Abl and Src kinases, we identified Tec Btk Tec, but not Itk, as major binders dasatinib. The activity was inhibited nanomolar concentrations in vitro cultured gatekeeper residue critical determinant...
The SH2 domain of cytoplasmic tyrosine kinases can enhance catalytic activity and substrate recognition, but the molecular mechanisms by which this is achieved are poorly understood. We have solved structure prototypic SH2-kinase unit human Fes kinase, appears specialized for positive signaling. In its active conformation, tightly interacts with kinase N-terminal lobe positions alphaC helix in an configuration through essential packing electrostatic interactions. This interaction stabilized...
The tyrosine kinase Bcr-Abl causes chronic myeloid leukemia and is the cognate target of inhibitors like imatinib. We have charted protein-protein interaction network by a 2-pronged approach. Using monoclonal antibody we first purified endogenous protein complexes from CML K562 cell line characterized set most tightly-associated interactors MS. Nine were subsequently subjected to tandem affinity purifications/MS analysis obtain molecular some hundred cellular proteins. resulting revealed...
Chronic myelogenous leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl and treated with inhibitor (TKI) imatinib. However, emerging TKI resistance prevents complete cure. Therefore, alternative strategies targeting regulatory modules of in addition to site are strongly desirable. Here, we show that an intramolecular interaction between SH2 domains both necessary sufficient for high catalytic activity enzyme. Disruption this interface led inhibition downstream...
Abl kinases are prototypic cytoplasmic tyrosine and involved in a variety of chromosomal aberrations different cancers. This causes the expression fusion proteins, such as Bcr-Abl, that constitutively activated drivers tumorigenesis. Over past decades, biochemical functional studies on molecular mechanisms regulation have gone hand with progression our structural understanding autoinhibited active conformations. In parallel, oncoproteins become prime targets for cancer therapy, using...
The two major isoforms of the oncogenic Bcr–Abl tyrosine kinase, p210 and p190, are expressed upon Philadelphia chromosome translocation. is hallmark chronic myelogenous leukemia, whereas p190 occurs in majority B-cell acute lymphoblastic leukemia. Differences protein interactions activated signaling pathways that may be associated with different diseases driven by unknown. We have performed a quantitative comparative proteomics study p190. Strong differences interactome phosphoproteome were...
Biotin-based labeling strategies are widely employed to study protein-protein interactions, subcellular proteomes and post-translational modifications, as well as, used in drug discovery. While the high affinity of streptavidin for biotin greatly facilitates capture biotinylated proteins, it still presents a challenge, currently employed, recovery peptides. Here we describe strategy designated Biotinylation Site Identification Technology (BioSITe) peptides LC-MS/MS analyses. We demonstrate...
Significance Protein–protein interactions are essential for cellular regulation, but how changes in individual influence physiology or cause disease remains poorly characterized. Although selective and potent inhibitors of protein–protein powerful tools, developing such reagents is challenging. This because signaling networks composed members highly conserved protein domain families, with the Src-homology 2 (SH2) as an archetype. To address this challenge, we used design to successfully...
Abstract Background Imatinib represents the first in a class of drugs targeted against chronic myelogenous leukemia to enter clinic, showing excellent efficacy and specificity for Abl, Kit, PDGFR kinases. Recent screens carried out find off-target proteins that bind imatinib identified oxidoreductase NQO2, flavoprotein is phosphorylated cell line. Results We examined inhibition NQO2 activity by Abl kinase inhibitors imatinib, nilotinib, dasatinib, obtained IC 50 values 80 nM, 380 >100 μM,...