A5013934686- Microbial Natural Products and Biosynthesis
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Cell Image Analysis Techniques
- Computational Drug Discovery Methods
- Epigenetics and DNA Methylation
- Hedgehog Signaling Pathway Studies
- Cancer-related gene regulation
- Tryptophan and brain disorders
- Protein Degradation and Inhibitors
- RNA and protein synthesis mechanisms
- Cancer-related Molecular Pathways
- Advanced Fluorescence Microscopy Techniques
- Chemical synthesis and alkaloids
- Chromatin Remodeling and Cancer
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- Autophagy in Disease and Therapy
- Marine Sponges and Natural Products
- RNA Interference and Gene Delivery
- Microbial Metabolism and Applications
- Microtubule and mitosis dynamics
- Sarcoma Diagnosis and Treatment
- CAR-T cell therapy research
- Testicular diseases and treatments
Max Planck Institute of Molecular Physiology
2016-2025
Max Planck Society
2006-2023
Max-Planck-Institut für Kohlenforschung
2016
Heinrich Heine University Düsseldorf
2005-2006
Ruhr University Bochum
2006
BG University Hospital Bergmannsheil Bochum
2006
Children with Cancer UK
2005
Neurology, Inc
2005
Children's Hospital of Los Angeles
2005
University of Southern California
2005
Abstract Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding molecular recognition of RNA structures small molecules. Here we studied patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded structures. Mapping these interaction landscapes across human transcriptome defined structure–activity relationships. Although RNA-binding compounds that bind...
Aberrant activation of wingless (Wnt) signaling is involved in the pathogenesis various cancers. Recent studies suggested a role Wnt gliomas, most common primary brain tumors. We investigated 70 gliomas different malignancy grades for promoter hypermethylation 8 genes encoding members secreted frizzled-related protein (SFRP1, SFRP2, SFRP4, SFRP5), dickkopf (DKK1, DKK3) and naked (NKD1, NKD2) families pathway inhibitors. All tumors were additionally analyzed mutations exon 3 beta-catenin gene...
Caseinolytic protease P (ClpP) represents a central bacterial degradation machinery that is involved in cell homeostasis and pathogenicity. The functional role of ClpP has been studied by genetic knockouts through the use beta-lactones, which remain only specific inhibitors discovered to date. Beta-lactones have served as chemical tools manipulate several organisms; however, their potency, selectivity stability limited. Despite detailed structural insights into composition conformational...
Abstract Natural product structure and fragment-based compound development inspire pseudo-natural design through different combinations of a given natural fragment set to classes expected be chemically biologically diverse. We describe the synthetic combination fragment-sized products quinine, quinidine, sinomenine, griseofulvin with chromanone or indole-containing fragments provide 244-member collection. Cheminformatic analyses reveal that resulting eight are diverse share both drug-...
Abstract Bioactive compound design based on natural product (NP) structure may be limited because of partial coverage NP‐like chemical space and biological target space. These limitations can overcome by combining NP‐centered strategies with fragment‐based through combination NP‐derived fragments to afford structurally unprecedented “pseudo‐natural products” (pseudo‐NPs). The design, synthesis, evaluation a collection indomorphan pseudo‐NPs that combine biosynthetically unrelated indole‐...
Abstract Avapritinib is the only potent and selective inhibitor approved for treatment of D842V-mutant gastrointestinal stromal tumors (GIST), most common primary mutation platelet-derived growth factor receptor α (PDGFRA). The approval was based on NAVIGATOR trial, which revealed overall response rates more than 90%. Despite this transformational activity, patients eventually progress, mostly due to acquired resistance mutations or following discontinuation neuro-cognitive side effects....
Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary
Abstract Chemical proteomics is widely applied in small‐molecule target identification. However, general it does not identify non‐protein targets, and thus, alternative methods for identification are high demand. We report the discovery of autophagy inhibitor autoquin its molecular mode action using image‐based morphological profiling cell painting assay. A compound‐induced fingerprint representing changes 579 cellular parameters revealed that accumulates lysosomes inhibits their fusion with...
Unbiased morphological profiling of bioactivity, for example, in the cell painting assay (CPA), enables identification a small molecule's mode action based on its similarity to bioactivity reference compounds, irrespective biological target or chemical similarity. This is particularly important molecules with nonprotein targets as these are rather difficult identify widely employed target-identification methods. We using CPA compounds that biosimilar iron chelator deferoxamine. Structurally...
Transcriptional enhanced associate domain (TEAD) transcription factors together with coactivators and corepressors modulate the expression of genes that regulate fundamental processes, such as organogenesis cell growth, elevated TEAD activity is associated tumorigenesis. Hence, novel modulators methods for their identification are in high demand. We describe development a new "thiol conjugation assay" small molecules bind to central pocket. The assay monitors prevention covalent binding...
Metabolic alterations in cancer precipitate associated dependencies that can be therapeutically exploited. To meet this goal, natural product-inspired small molecules provide a resource of invaluable chemotypes. Here, we identify orpinolide, synthetic withanolide analog with pronounced antileukemic properties, via orthogonal chemical screening. Through multiomics profiling and genome-scale CRISPR-Cas9 screens, orpinolide disrupts Golgi homeostasis mechanism requires active...
Abstract The efficient exploration of biologically relevant chemical space is essential for the discovery bioactive compounds. A molecular design principle that possesses both biological relevance and structural diversity may more efficiently lead to compound collections are enriched in diverse bioactivities. Here pseudo-natural product (PNP) strategy, which combines PNP concept with synthetic diversification strategies from diversity-oriented synthesis, reported. collection was synthesized...
Cancer cells display widespread changes in DNA methylation that may lead to genetic instability by global hypomethylation and aberrant silencing of tumor suppressor genes focal hypermethylation. In turn, altered patterns have been used identify putative genes.In a screening approach, we identified ECRG4 as differentially methylated gene. We analyzed different cancer for promoter COBRA bisulfite sequencing. Gene expression analysis was carried out semi-quantitative RT-PCR. The coding region...
Small molecule inhibitors of pre-mRNA splicing are important tools for identifying new spliceosome assembly intermediates, allowing a finer dissection dynamics and function. Here, we identified small that inhibits human at an intermediate stage during conversion pre-catalytic spliceosomal B complexes into activated Bact complexes. Characterization the stalled (designated B028) revealed U4/U6 snRNP proteins released activation before U6 Lsm B-specific proteins, recruitment and/or stable...
Abstract Natural product (NP) structures are a rich source of inspiration for the discovery new biologically relevant chemical matter. In natural inspired pseudo‐NPs, NP‐derived fragments combined de novo in unprecedented arrangements. Described here is design and synthesis 155‐member pyrroquinoline pseudo‐NP collection which characteristic tetrahydroquinoline pyrrolidine NP classes with eight different connectivities regioisomeric Cheminformatic analysis biological evaluation compound by...
Modulation of protein–RNA interaction (PRI) using small molecules is a promising strategy to develop therapeutics. LIN28 an RNA-binding protein that blocks the maturation tumor suppressor let-7 microRNAs. Herein, we performed fluorescence polarization-based screening and identified trisubstituted pyrrolinones as small-molecule inhibitors disrupting LIN28–let-7 interaction. The most potent compound C902 showed dose-dependent inhibition in EMSA validation assay, enhanced thermal stability cold...
Abstract Profiling approaches have been increasingly employed for the characterization of disease‐relevant phenotypes or compound perturbation as they provide a broad, unbiased view on impaired cellular states. We report that morphological profiling using cell painting assay (CPA) can detect modulators de novo pyrimidine biosynthesis and dihydroorotate dehydrogenase (DHODH) in particular. The CPA differentiate between impairment folate metabolism, which both affect nucleotide pools....
Our understanding of sterol transport proteins (STPs) has increased exponentially in the last decades with advances cellular and structural biology these important proteins. However, small molecule probes have only recently been developed for a few selected STPs. Here we describe synthesis evaluation potential proteolysis-targeting chimeras (PROTACs) based on inhibitors STP Aster-A. Based reported Aster-A inhibitor autogramin-2, ten PROTACs were synthesized. Pomalidomide-based functioned as...
Abstract The pseudo‐natural product (pseudo‐NP) concept aims to combine NP fragments in arrangements that are not accessible through known biosynthetic pathways. resulting compounds retain the biological relevance of NPs but yet linked bioactivities and may therefore be best evaluated by unbiased screening methods identification unexpected or unprecedented bioactivities. Herein, various combined with a tricyclic core connectivity via interrupted Fischer indole dearomatization reactions...