A5077558723- Cytomegalovirus and herpesvirus research
- Cancer-related Molecular Pathways
- Herpesvirus Infections and Treatments
- Advanced Breast Cancer Therapies
- Cancer Mechanisms and Therapy
- 14-3-3 protein interactions
- HIV Research and Treatment
- Immune cells in cancer
- Ubiquitin and proteasome pathways
- interferon and immune responses
- Advanced Fluorescence Microscopy Techniques
- Melanoma and MAPK Pathways
- Advanced Biosensing Techniques and Applications
- Angiogenesis and VEGF in Cancer
- Histone Deacetylase Inhibitors Research
- Immunotherapy and Immune Responses
- Advanced Proteomics Techniques and Applications
- Mycobacterium research and diagnosis
- RNA regulation and disease
- Epigenetics and DNA Methylation
- Microbial Natural Products and Biosynthesis
- Protein Kinase Regulation and GTPase Signaling
- Protein Tyrosine Phosphatases
- Chronic Lymphocytic Leukemia Research
- RNA modifications and cancer
Lead Discovery Center (Germany)
2014-2024
Phenex Pharmaceuticals (Germany)
2005-2023
UNSW Sydney
2009
Neovii Biotech (Germany)
2008
Agilent Technologies (Germany)
2007
Max Planck Society
1999-2002
Max Planck Institute of Biochemistry
2002
University of Bayreuth
1999
The death of a cell is an inevitable part its biology. During homeostasis, most cells die through apoptosis. If homeostasis disturbed, can switch to proinflammatory forms death, such as necroptosis, pyroptosis, or NETosis. We demonstrate that the formation neutrophil extracellular traps (NETs), special form releases chromatin structures space, dependent on gasdermin D (GSDMD). GSDMD pore-forming protein and executor pyroptosis. screened chemical library found small molecule based...
Abstract Selective inhibition of exclusively transcription‐regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY‐958, optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited best overall profile vitro vivo, including high...
The cyclin-dependent kinase CDK9 is an important therapeutic target but currently available inhibitors exhibit low specificity and/or narrow windows. Here we have used a new highly specific inhibitor, LDC000067 to interrogate gene control mechanisms mediated by CDK9.The selectivity of was established in functional assays. Functions expression were assessed with vitro transcription experiments, single analyses and genome-wide profiling. Cultures mouse embryonic stem cells, HeLa several cancer...
ABSTRACT Protein kinases represent central and multifunctional regulators of a balanced virus-host interaction. Cyclin-dependent protein kinase 7 (CDK7) plays crucial regulatory roles in cell cycle transcription, both connected with the replication many viruses. Previously, we developed CDK7 inhibitor, LDC4297, that inhibits vitro nano-picomolar range. Novel data from kinome-wide evaluation (>330 profiled ) demonstrate selectivity. Importantly, provide first evidence for antiviral...
Cyclin-dependent kinase 7 (CDK7) activates cell cycle CDKs and is a member of the general transcription factor TFIIH. Although there substantial evidence for an active role CDK7 in mRNA synthesis associated processes, degree its influence on global gene-specific mammalian species unclear. In current study, we utilize two novel inhibitors with high specificity to demonstrate restricted but robust impact gene vivo vitro-reconstituted reactions. We distinguish between relative low- high-dose...
Knowledge about molecular drug action is critical for the development of protein kinase inhibitors cancer therapy. Here, we establish a chemical proteomic approach to profile anticancer SU6668, which was originally designed as selective inhibitor receptor tyrosine kinases involved in tumor vascularization. By employing immobilized SU6668 affinity capture cellular targets combination with mass spectrometry, identified previously unknown including Aurora and TANK-binding 1. Importantly, cell...
Neuroinflammation is a hallmark of neurological disorders and accompanied by the production neurotoxic agents such as nitric oxide. We used stem cell-based phenotypic screening identified small molecules that directly protected neurons from neuroinflammation-induced degeneration. demonstrate inhibition CDK5 involved in, but not sufficient for, neuroprotection. Instead, additional GSK3β required to enhance neuroprotective effects inhibition, which was confirmed using short hairpin...
The repertoire of currently available antiviral drugs spans therapeutic applications against a number important human pathogens distributed worldwide. These include cases the pandemic severe acute respiratory coronavirus type 2 (SARS-CoV-2 or COVID-19), immunodeficiency virus 1 (HIV-1 AIDS), and pregnancy- posttransplant-relevant cytomegalovirus (HCMV). In almost all cases, approved therapies are based on direct-acting antivirals (DAAs), but their benefit, particularly in long-term...
Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number oncogenic drivers are directly druggable. By interrogating activity 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells specifically killed by CDK9 inhibition (CDK9i) and depend on Cyclin-T1 expression. We show CDK9i leads to robust induction apoptosis markers DNA damage response in NMC cells. While both bromodomain over time result reduced Myc protein...
Human cytomegalovirus (HCMV) is a human pathogenic herpesvirus associated with variety of clinical symptoms. Current antiviral therapy not always effective, so that improved drug classes and drug-targeting strategies are needed. Particularly host-directed antivirals, including pharmaceutical kinase inhibitors (PKIs), may help to overcome problems resistance. Here, we focused on utilizing selection clinically relevant PKIs determined their anticytomegaloviral efficacies. Particularly,...
Replication of human cytomegalovirus (HCMV) is subject to regulation by cellular protein kinases. Recently, we and others reported that inhibition cyclin-dependent kinases (CDKs) or the viral CDK ortholog pUL97 can induce intranuclear speckled aggregation mRNA export factor, pUL69. Here provide first evidence for a direct regulatory role CDKs on pUL69 functionality. Although replication all HCMV strains was dependent activity, found strain-specific differences in amount inhibitor-induced...
Colony-stimulating factor-1 receptor (CSF1R) is a tyrosine kinase that controls the differentiation and maintenance of most tissue-resident macrophages, inhibition CSF1R has been suggested as possible therapy for range human disorders. Herein, we present synthesis, development, structure–activity relationship series highly selective pyrrolo[2,3-d]pyrimidines, showing subnanomolar enzymatic this with excellent selectivity toward other kinases in platelet-derived growth factor (PDGFR) family....
The activation of p38 MAPK by dual phosphorylation aggravates myocardial ischemic injury and depresses cardiac contractile function. SB203580, an ATP-competitive inhibitor other kinases, prevents this during ischemia. Studies in non-cardiac tissue have shown receptor-interacting protein 2 (RIP2) lies upstream MAPK, is SB203580-sensitive ischemia-responsive, injury. We therefore examined the RIP2-p38 signaling axis heart. Adenovirus-driven expression wild-type RIP2 adult rat ventricular...
Cyclin-dependent protein kinases (CDKs) are important regulators of cellular processes and functionally integrated into the replication human cytomegalovirus (HCMV). Recently, a regulatory impact CDK activity on viral mRNA export factor pUL69 was shown. Here, specific aspects mode interaction between CDK9/cyclin T1 described. Intracellular localization studied in presence novel selective CDK9 inhibitor, R22, which exerts anti-cytomegaloviral vitro. A pronounced R22-induced formation nuclear...
The RON tyrosine kinase receptor is under investigation as a novel target in pancreatic cancer. While mutations are uncommon, isoforms produced cancer cells via variety of mechanisms. In this study we sought to: 1) characterize isoform expression cancer, 2) investigate mechanisms that regulate expression, and 3) determine how various effect gene oncogenic phenotypes responses to directed therapies. We quantified transcripts human found levels 2500 fold normal pancreas with comprising nearly...
In this work, we demonstrate that the indole-oxazole-pyrrole framework of breitfussin family natural products is a promising scaffold for kinase inhibition. Six new halogenated products, C–H (3 – 8) were isolated and characterized from Arctic, marine hydrozoan Thuiaria breitfussi. The structures two also confirmed by total synthesis. Two breitfussins 4) found to selectively inhibit survival several cancer cell lines, with lowest IC50 value 340 nM measured against drug-resistant triple...
The colony-stimulating factor 1 receptor (CSF1R) plays an important role in the regulation of many inflammatory processes, and overexpression kinase is implicated several disease states. Identifying selective, small-molecule inhibitors CSF1R may be a crucial step toward treating these disorders. Through modelling, synthesis, systematic structure-activity relationship study, we have identified number potent highly selective purine-based CSF1R. optimized 6,8-disubstituted antagonist, compound...
Human cytomegalovirus (HCMV) infection is shaped by a tightly regulated interplay between viral and cellular proteins. Distinct kinase activities, such as the cyclin-dependent ortholog (vCDK) pUL97 CDK7 are both crucial for efficient replication. Previously, we reported that kinases, vCDK/pUL97 CDK7, interact with cyclin H, thereby achieving an enhanced level of activity overall functionality in Here provide variety novel results, generated on methodologically extended basis, present concept...
The duration and the magnitude of mitogen-activated protein kinase (MAPK) activation specifies signal identity thus allows regulation diverse cellular functions by same cascade. A tight finely tuned MAPK activity is therefore critical for definition a specific response. We investigated role tyrosine-specific phosphatases (PTPs) in ERK5. Although unique its structure, ERK5 activated analogy to other MAPKs dual phosphorylation threonine tyrosine residues motif. In this study we concentrated on...