Birgit Duempelfeld
A5022915278- PARP inhibition in cancer therapy
- Biosimilars and Bioanalytical Methods
- Health Systems, Economic Evaluations, Quality of Life
- Wnt/β-catenin signaling in development and cancer
- Cytokine Signaling Pathways and Interactions
- Mass Spectrometry Techniques and Applications
- Cancer-related gene regulation
- Biochemical and Molecular Research
- Chronic Lymphocytic Leukemia Research
- NF-κB Signaling Pathways
- Mechanisms of cancer metastasis
- interferon and immune responses
- PI3K/AKT/mTOR signaling in cancer
- Metabolomics and Mass Spectrometry Studies
- Advanced Proteomics Techniques and Applications
- Lipoproteins and Cardiovascular Health
- Cancer, Lipids, and Metabolism
GlaxoSmithKline (Germany)
2017-2021
The serine/threonine protein kinase TBK1 (Tank-binding Kinase-1) is a noncanonical member of the IkB (IKK) family. This regulates signaling pathways in innate immunity, oncogenesis, energy homeostasis, autophagy, and neuroinflammation. Herein, we report discovery characterization novel potent highly selective inhibitor, GSK8612. In cellular assays, this small molecule inhibited toll-like receptor (TLR)3-induced interferon regulatory factor (IRF)3 phosphorylation Ramos cells type I (IFN)...
<p>Expression proteomic signature</p>
<p>Photo affinity labelling (PAL)</p>
<p>Steroidomics</p>
<p>Transcriptomic signature</p>
<p>Supplementary Materials and Methods</p>
<p>PARP1 PARP2 engagement (ITDR)</p>
<p>panPARP matrix (affinity enrichment chemoproteomics)</p>
<p>Selectivity profile live cells (2D-TPP)</p>
<p>Niraparib matrix (affinity enrichment chemoproteomics)</p>
<p>Co-inhibition of PARP and cholesterol biosynthesis pathway increase efficiency tumor cell killing</p>
<p>Niraparib specific modulation of cholesterol biosynthesis pathway in cancer cell lines</p>
<p>Selectivity profiling and Niraparib-LSS interaction</p>
<p>Niraparib specific modulation of expression levels proteins involved in cholesterol biosynthesis pathway cancer cell lines (proteomics)</p>
<p>Detection of 24,25-epoxycholesterol</p>
<p>Kinobead assay (affinity enrichment chemoproteomics)</p>
The availability of high quality probes for specific protein targets is fundamental to the investigation their function and validation as therapeutic targets. We report utilization a dedicated chemoproteomic assay platform combining affinity enrichment technology with high-resolution mass spectrometry discovery novel nicotinamide isoster, tetrazoloquinoxaline 41, highly potent selective tankyrase inhibitor. also describe use 41 investigate biology tankyrase, revealing compound induced growth...
Abstract An in-depth multiomic molecular characterization of PARP inhibitors revealed a distinct poly-pharmacology niraparib (Zejula) mediated by its interaction with lanosterol synthase (LSS), which is not observed other inhibitors. Niraparib, in similar way to the LSS inhibitor Ro-48-8071, induced activation 24,25-epoxysterol shunt pathway, regulatory signaling branch cholesterol biosynthesis pathway. Interestingly, combination an that does bind LSS, such as olaparib, had additive effect...
<div>Abstract<p>An in-depth multiomic molecular characterization of PARP inhibitors revealed a distinct poly-pharmacology niraparib (Zejula) mediated by its interaction with lanosterol synthase (LSS), which is not observed other inhibitors. Niraparib, in similar way to the LSS inhibitor Ro-48-8071, induced activation 24,25-epoxysterol shunt pathway, regulatory signaling branch cholesterol biosynthesis pathway. Interestingly, combination an that does bind LSS, such as olaparib,...
<p>Selectivity profiling and Niraparib-LSS interaction</p>
<p>Detection of 24,25-epoxycholesterol</p>
<div>Abstract<p>An in-depth multiomic molecular characterization of PARP inhibitors revealed a distinct poly-pharmacology niraparib (Zejula) mediated by its interaction with lanosterol synthase (LSS), which is not observed other inhibitors. Niraparib, in similar way to the LSS inhibitor Ro-48-8071, induced activation 24,25-epoxysterol shunt pathway, regulatory signaling branch cholesterol biosynthesis pathway. Interestingly, combination an that does bind LSS, such as olaparib,...
<p>Co-inhibition of PARP and cholesterol biosynthesis pathway improves efficiency in tumor cell killing. <b>A,</b> Viability (ATP levels) HCC70 triple-negative breast cancer (TNBC) line after 7-day treatment with niraparib (6.25 μmol/L) olaparib as a single agent or combination LSS inhibitor Ro-48-8071 (300 nmol/L). Mean (<i>n</i> = 3) for four independent biological experiments is shown (linear mixed-effect model TukeyHSD contrasts, ****, <i>P</i> ≤...
<p>panPARP matrix (affinity enrichment chemoproteomics)</p>