A5101961869- Melanoma and MAPK Pathways
- Cytokine Signaling Pathways and Interactions
- Biochemical and Molecular Research
- Synthesis and biological activity
- Carbohydrate Chemistry and Synthesis
- X-ray Diffraction in Crystallography
- Pharmacological Effects of Natural Compounds
- Synthesis of Tetrazole Derivatives
- Synthesis and Biological Evaluation
- Rheumatoid Arthritis Research and Therapies
- Synthesis and properties of polymers
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Cancer therapeutics and mechanisms
- Crystallization and Solubility Studies
- Microtubule and mitosis dynamics
- Membrane Separation and Gas Transport
- Peptidase Inhibition and Analysis
- Click Chemistry and Applications
- Cancer-related Molecular Pathways
- Advanced Photocatalysis Techniques
- DNA Repair Mechanisms
- Catalytic Cross-Coupling Reactions
- Perovskite Materials and Applications
- Conducting polymers and applications
- Covalent Organic Framework Applications
University of Tübingen
2016-2025
German Cancer Research Center
2022
Heidelberg University
2022
University of Wuppertal
2006-2021
TH Bingen University of Applied Sciences
2013
University of Potsdam
2002
Max Planck Society
2000
Max Planck Institute for Polymer Research
2000
Abstract Two‐dimensional (2D) transition‐metal dichalcogenides (TMDs) have drawn much attention due to their unique physical and chemical properties. Using TMDs as templates for the generation of 2D sandwich‐like materials with remarkable properties still remains a great challenge poor solvent processability. Herein, MoS 2 ‐coupled conjugated microporous polymers (M‐CMPs) high specific surface area were successfully developed by using functionalized nanosheets template. As‐prepared M‐CMPs...
Janus kinases (JAKs) are a family of cytoplasmatic tyrosine that attractive targets for the development anti-inflammatory drugs given their roles in cytokine signaling. One question regarding JAKs and inhibitors remains under intensive debate is whether JAK should be isoform selective. Since JAK3 functions restricted to immune cells, an isoform-selective inhibitor could especially valuable achieve clinically more useful precise effects. However, high degree structural conservation makes...
Colorectal cancer (CRC) constitutes the second leading cause of cancer-related death worldwide and advanced CRCs are resistant to targeted therapies, chemotherapies immunotherapies. p38α (Mapk14) has been suggested as a therapeutic target in CRC; however, available inhibitors only allow for insufficient inhibition. Here we describe unique class with ultralong residence times (designated ULTR-p38i) that robustly inhibit downstream signaling induce distinct biological phenotypes. ULTR-p38i...
Abstract Target residence time plays a crucial role in the pharmacological activity of small molecule inhibitors. Little is known, however, about underlying causes inhibitor at molecular level, which complicates drug optimization processes. Here, we employ all-atom dynamics simulations (~400 μs total) to gain insight into binding modes two structurally similar p38α MAPK inhibitors (type I and type I½) with short long times that otherwise show nearly identical inhibitory activities low...
Janus kinases are major drivers of immune signaling and have been the focus anti-inflammatory drug discovery for more than a decade. Because invariable colocalization JAK1 JAK3 at cytokine receptors, question if selective inhibition is sufficient to effectively block downstream has highly controversial. Recently, we discovered covalent-reversible inhibitor FM-381 (23) featuring high isoform kinome selectivity. Crystallography revealed that this induces an unprecedented binding pocket by...
Abstract Incorporation of the donor–acceptor structure an alternating conjugated copolymer into a rigid ladder polymer backbone is reported. The resulting polymers show optical features typical polymers, but present increased Stokes shift if compared to their non‐polar counterparts. This behavior reflects occurrence charge transfer processes during excitation and leads positive solvatochromism.
Abstract Despite intensive efforts to improve early cancer detection, date 30% of all solid tumors are still diagnosed at a metastasized and incurable stage. Molecular mechanisms underlying metastasis poorly understood, thus far there no strategies suppress it. Here, using high-plex spatial protein profiling human murine tumours as well functional studies in mouse models, we show that intratumoral microenvironmental stress factors induce senescence apoptosis resistant tumor cells, resulting...
Synthesis of processable, aromatic pyridine-containing polymers has always been a great challenge.
The Janus kinases (JAKs) are a family of cytosolic tyrosine crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets the treatment inflammatory and myeloproliferative disorders, two inhibitors, tofacitinib ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within JAK remains major issue. Both approved compounds share common 7H-pyrrolo[2,3-d]pyrimidine hinge binding motif, little is known about modifications...
Abstract Two‐dimensional (2D) transition‐metal dichalcogenides (TMDs) have drawn much attention due to their unique physical and chemical properties. Using TMDs as templates for the generation of 2D sandwich‐like materials with remarkable properties still remains a great challenge poor solvent processability. Herein, MoS 2 ‐coupled conjugated microporous polymers (M‐CMPs) high specific surface area were successfully developed by using functionalized nanosheets template. As‐prepared M‐CMPs...
p38 mitogen-activated protein kinases are key mediators of environmental stress response and promising targets for treatment inflammatory diseases cancer. Numerous efforts have led to the discovery several potent inhibitors; however, so far no highly selective type-II inhibitors been reported. We previously identified VPC-00628 as a inhibitor p38α/β with few off-targets. Here we analyzed chemical building blocks that played role in achieving potency selectivity through targeting an inactive...
The nonreceptor tyrosine TEC kinases are key regulators of the immune system and play a crucial role in pathogenesis diverse hematological malignancies. In contrast to substantial efforts inhibitor development for Bruton’s kinase (BTK), specific inhibitors other kinases, including bone marrow on chromosome X (BMX), remain sparse. Here we present novel class dual BMX/BTK inhibitors, which were designed from irreversible Janus (JAK) 3 targeting cysteine located within solvent-exposed front...
Abstract Summary: The first examples of the dye‐coated semi‐conducting polymer nanoparticles as well experiments to demonstrate excitation energy transfer from excited chromophor nanoparticle fluorescent dye are described. We have demonstrated that blue fluorescence polyfluorene is only slightly quenched after deposition. However, a new emission band surface‐bound (Rhodamine 6G or Rhodamine TM) appears in wavelength region 530–600 nm. These results clearly indicate an effective PF...
A solution-phase parallel synthesis of triazole-derived ruxolitinib analogues was developed in the current study. The method employs copper-catalyzed azide–alkyne cycloaddition to build up central triazole template. Product isolation by precipitation and centrifugation is straightforward yields high purity compounds suited for biological profiling. simple protocol accessing terminal alkyne precursors established a library ruxolitinib-like triazoles featuring diverse functional groups...
The recent disclosure of type I 1/2 inhibitors for p38α MAPK demonstrated how the stabilization R-spine can be used as a strategy to greatly increase target residence time (TRT) inhibitors. Herein, first time, we describe N-acylhydrazone and selenophene residues spine motifs, yielding metabolically stable with high potency on enzymatic, NanoBRET, whole blood assays, improved metabolic stability, prolonged TRT.
The ATM kinase is a promising target in cancer treatment as an important regulator of the cellular response to DNA double-strand breaks. In this work, we present new class specific benzimidazole-based inhibitors with picomolar potency against isolated enzyme and favorable selectivity within relative PIKK PI3K kinases. We could identify two inhibitor subgroups significantly different physicochemical properties, which developed simultaneously. These efforts lead numerous highly active...
Efficient and ambient synthesis of aromatic polyimides (PIs) from readily available starting materials remains a very challenging task in polymer chemistry. Herein, we report for the first time robust, one-step organo-soluble functional PIs. Room temperature, metal-free, superacid (TFSA)-catalyzed step polymerization aryl-terminated diimides with carbonyl compounds (2,2,2-trifluoroacetophenone indoline-2,3-dione (isatin)) afforded 14 high-molecular-weight, linear, film-forming The effect...
The histone kinase PRK1 has been identified as a potential target to combat prostate cancer but selective inhibitors are lacking. US FDA -approved JAK1-3 inhibitor tofacitinib also potently inhibits in vitro.We show that cellular setting. Using starting point for structure-activity relationship studies, we more potent and another compared with tofacitinib. Furthermore, found two PRK1/JAK3-selectivity hotspots.The the selectivity hotspots lay basis development of inhibitors. identification...
Glycogen synthase kinase-3β (GSK-3β) represents a relevant drug target for the treatment of neurodegenerative pathologies including Alzheimer’s disease. We herein report on optimization novel class GSK-3β inhibitors based tofacitinib-derived screen hit 3-((3R,4R)-3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (1). synthesized series 19 7-chloro-9H-pyrimido[4,5-b]indole-based derivatives and studied their structure–activity relationships...
Abstract Incorporation of the donor–acceptor structure an alternating conjugated copolymer into a rigid ladder polymer backbone is reported. The resulting polymers show optical features typical polymers, but present increased Stokes shift if compared to their non‐polar counterparts. This behavior reflects occurrence charge transfer processes during excitation and leads positive solvatochromism.
Modulation of Janus kinase/signal transducer and activator transcription (JAK/STAT) signaling is a promising method treating autoimmune diseases, the profound potency clinical compounds makes this mode action particularly attractive. Other questions that remain unanswered also include: What ideal selectivity between JAK1 JAK3? Which cells are most relevant to JAK blockade? And what tissue distribution pattern for addressing specific conditions? We hypothesized JAK3 low-dose effects...