A5053031388- Cell Image Analysis Techniques
- Computational Drug Discovery Methods
- Advanced Biosensing Techniques and Applications
- Cancer-related Molecular Pathways
- Cancer, Hypoxia, and Metabolism
- Ubiquitin and proteasome pathways
- Microtubule and mitosis dynamics
- Metabolism, Diabetes, and Cancer
- Enzyme Structure and Function
- Pharmacogenetics and Drug Metabolism
- Advanced Fluorescence Microscopy Techniques
- Medical Imaging Techniques and Applications
- Click Chemistry and Applications
- Biosimilars and Bioanalytical Methods
- Peroxisome Proliferator-Activated Receptors
- Neonatal Health and Biochemistry
- Advanced MIMO Systems Optimization
- Liver physiology and pathology
- Eicosanoids and Hypertension Pharmacology
- Liver Disease Diagnosis and Treatment
- Microbial metabolism and enzyme function
- PI3K/AKT/mTOR signaling in cancer
- Research Data Management Practices
- Protein Degradation and Inhibitors
- Single-cell and spatial transcriptomics
Goethe University Frankfurt
2020-2023
Structural Genomics Consortium
2023
Benzoxazepinones have been extensively studied as exclusively selective RIP kinase 1 inhibitors. This scaffold binds a type-III inhibitor targeting the αC-out/DFG-out conformation. inactive conformation results in large expansion of back pocket, that has also reported for LIM kinases. Scaffold hopping is common design orthosteric inhibitors, but not explored allosteric mainly due to typically exclusive selectivity type III Here, we hypothesized shared structural properties LIMKs and RIPKs...
Phenotypical screening is a widely used approach in drug discovery for the identification of small molecules with cellular activities. However, functional annotation identified hits often poses challenge. The development narrow or exclusive target selectivity such as chemical probes and chemogenomic (CG) libraries, greatly diminishes this challenge, but non-specific effects caused by compound toxicity interference basic functions still pose problem to associate phenotypic readouts molecular...
Background and Aims: The liver has a remarkable capacity to regenerate, which is sustained by the ability of hepatocytes act as facultative stem cells that, while normally quiescent, re-enter cell cycle after injury. Growth factor signaling indispensable in rodents, whereas Wnt/β-catenin not required for effective tissue repair. However, molecular networks that control human regeneration remain unclear. Methods: Organotypic 3D spheroid cultures primary or murine were used identify network...
Serine/threonine kinase 17A (death-associated protein kinase-related apoptosis-inducing 1─DRAK1) is a part of the death-associated (DAPK) family and belongs to so-called dark kinome. Thus, current state knowledge cellular function DRAK1 its involvement in pathophysiological processes very limited. Recently, has been implicated tumorigenesis glioblastoma multiforme (GBM) other cancers, but no selective inhibitors are available yet. To this end, we optimized pyrazolo[1,5-a]pyrimidine-based...
Abstract Non-alcoholic steatohepatitis (NASH) - a hepatic manifestation of the metabolic syndrome is multifactorial disease with alarming global prevalence. It involves steatosis, inflammation and fibrosis in liver, thus demanding multiple modes action for robust therapeutic efficacy. Aiming to fuse complementary validated anti-NASH strategies single molecule, we have designed systematically optimized scaffold triple activation farnesoid X receptor (FXR), peroxisome proliferator-activated...
The PCTAIRE subfamily belongs to the CDK (cyclin-dependent kinase) family and represents an understudied class of kinases dark kinome. They exhibit a highly conserved binding pocket are activated by cyclin Y binding. CDK16 is targeted plasma membrane after N-myristoylated expressed in post-mitotic tissues, such as brain testis. Dysregulation associated with several diseases, including breast, prostate, cervical cancer. Here, we used N-(1H-pyrazol-3-yl)pyrimidin-4-amine moiety from...
Well-characterized small molecules are essential tools for studying the biology and therapeutic relevance of a target protein. However, many compounds reported in literature routinely studied biomedical research lack potency selectivity required mechanistic cellular studies on function given Furthermore, commercially available often do not include useful developed by industry as part their development efforts, they frequently remain proprietary. The freely donated chemical probe (DCP)...
Discoidin domain receptors 1 and 2 (DDR1/2) play a central role in fibrotic disorders, such as renal pulmonary fibrosis, atherosclerosis, various forms of cancer. Potent selective inhibitors, so-called chemical probe compounds, have been developed to study DDR1/2 kinase signaling. However, these inhibitors showed undesired activity on other kinases the tyrosine protein receptor TIE or tropomyosin kinases, which are related angiogenesis neuronal toxicity. In this study, we optimized our...
Phenotypical screening is a widely used approach in drug discovery for the identification of small molecules with cellular activities. However, functional annotation identified hits often poses challenge. The development narrow or exclusive target selectivity such as chemical probes and chemogenomic (CG) libraries, greatly diminishes this challenge, but non-specific effects caused by compound toxicity interference basic functions still problem to associate phenotypic readouts molecular...
Building on the pyrazolopyrimidine CK2 (casein kinase 2) inhibitor scaffold, we designed a small targeted library. Through comprehensive evaluation of selectivity, identified 24 (SGC-CK2-1) as highly potent and cell-active chemical probe with exclusive selectivity for both human isoforms. Remarkably, despite years research pointing to key driver in cancer, our did not elicit broad antiproliferative phenotype >90% >140 cell lines when tested dose-response. While many publications have...
ABSTRACT Salt-inducible kinases 1-3 (SIK1-3) are key regulators of the LKB1-AMPK pathway and play an important role in cellular homeostasis. Dysregulation any three isoforms has been associated with tumorigenesis liver, breast, ovarian cancers. We have recently developed dual pan-SIK/group I p21-activated kinase (PAK) chemical probe MRIA9. However, inhibition cardiotoxicity vivo , which complicates use MRIA9 as a tool compound. Here, we present structure-based approach involving back-pocket...
Human Dihydroorotate dehydrogenase, which catalyses de novo pyrimidine biosynthesis, is an emerging target for treatment of infectious diseases, arthritis and cancer. In order to provide a chemical tool studying this key enzyme, we characterized IPP/CNRS-A017, highly potent, selective, cell-active inhibitor the human dehydrogenase (hDHODH). report, describe crystal structure IPP/CNRS-A017 in complex with hDHODH, providing inside into its binding mode. Additionally, further off-target...