6 results on '"Beatrice Bauer-Probst"'
Search Results
2. DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance
- Author
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Martin Schröder, Martin Renatus, Xiaoyou Liang, Fabian Meili, Thomas Zoller, Sandrine Ferrand, Francois Gauter, Xiaoyan Li, Frederic Sigoillot, Scott Gleim, Therese-Marie Stachyra, Jason R. Thomas, Damien Begue, Maryam Khoshouei, Peggy Lefeuvre, Rita Andraos-Rey, BoYee Chung, Renate Ma, Benika Pinch, Andreas Hofmann, Markus Schirle, Niko Schmiedeberg, Patricia Imbach, Delphine Gorses, Keith Calkins, Beatrice Bauer-Probst, Magdalena Maschlej, Matt Niederst, Rob Maher, Martin Henault, John Alford, Erik Ahrne, Luca Tordella, Greg Hollingworth, Nicolas H. Thomä, Anna Vulpetti, Thomas Radimerski, Philipp Holzer, Seth Carbonneau, and Claudio R. Thoma
- Subjects
Science - Abstract
Abstract Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.
- Published
- 2024
- Full Text
- View/download PDF
3. Fibroblast growth factor receptors as novel therapeutic targets in SNF5-deleted malignant rhabdoid tumors.
- Author
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Simon Wöhrle, Andreas Weiss, Moriko Ito, Audrey Kauffmann, Masato Murakami, Zainab Jagani, Anne Thuery, Beatrice Bauer-Probst, Flavia Reimann, Christelle Stamm, Astrid Pornon, Vincent Romanet, Vito Guagnano, Thomas Brümmendorf, William R Sellers, Francesco Hofmann, Charles W M Roberts, and Diana Graus Porta
- Subjects
Medicine ,Science - Abstract
Malignant rhabdoid tumors (MRTs) are aggressive pediatric cancers arising in brain, kidney and soft tissues, which are characterized by loss of the tumor suppressor SNF5/SMARCB1. MRTs are poorly responsive to chemotherapy and thus a high unmet clinical need exists for novel therapies for MRT patients. SNF5 is a core subunit of the SWI/SNF chromatin remodeling complex which affects gene expression by nucleosome remodeling. Here, we report that loss of SNF5 function correlates with increased expression of fibroblast growth factor receptors (FGFRs) in MRT cell lines and primary tumors and that re-expression of SNF5 in MRT cells causes a marked repression of FGFR expression. Conversely, siRNA-mediated impairment of SWI/SNF function leads to elevated levels of FGFR2 in human fibroblasts. In vivo, treatment with NVP-BGJ398, a selective FGFR inhibitor, blocks progression of a murine MRT model. Hence, we identify FGFR signaling as an aberrantly activated oncogenic pathway in MRTs and propose pharmacological inhibition of FGFRs as a potential novel clinical therapy for MRTs.
- Published
- 2013
- Full Text
- View/download PDF
4. Identification of the HECT E3 ligase UBR5 as a regulator of MYC degradation using a CRISPR/Cas9 screen
- Author
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Britta Knapp, Xiaoyou Liang, Beatrice Bauer-Probst, John S. Reece-Hoyes, Ines Barbosa, Angelica Mendiola, Tamara Zimmermann, Markus Reschke, Lina Schukur, Grainne Kerr, Claudio R. Thoma, Thomas Radimerski, Ole Niewoehner, Scott Gleim, Giorgio G. Galli, and Melivoia Rapti
- Subjects
Cell biology ,Ubiquitin-Protein Ligases ,Regulator ,lcsh:Medicine ,Apoptosis ,medicine.disease_cause ,Article ,Proto-Oncogene Proteins c-myc ,Neoplasms ,medicine ,Tumor Cells, Cultured ,Humans ,lcsh:Science ,Transcription factor ,Cancer ,chemistry.chemical_classification ,DNA ligase ,Multidisciplinary ,biology ,Cell growth ,lcsh:R ,Biological techniques ,Ubiquitination ,Ubiquitin ligase ,chemistry ,Oncology ,Cancer cell ,Proteolysis ,biology.protein ,lcsh:Q ,CRISPR-Cas Systems ,Carcinogenesis ,Genetic screen ,Protein Binding - Abstract
MYC oncoprotein is a multifunctional transcription factor that regulates the expression of a large number of genes involved in cellular growth, proliferation and metabolism. Altered MYC protein level lead to cellular transformation and tumorigenesis. MYC is deregulated in > 50% of human cancers, rendering it an attractive drug target. However, direct inhibition of this class of proteins using conventional small molecules is challenging due to their intrinsically disordered state. To discover novel posttranslational regulators of MYC protein stability and turnover, we established a genetic screen in mammalian cells by combining a fluorescent protein-based MYC abundance sensor, CRISPR/Cas9-based gene knockouts and next-generation sequencing. Our screen identifies UBR5, an E3 ligase of the HECT-type family, as a novel regulator of MYC degradation. Even in the presence of the well-described and functional MYC ligase, FBXW7, UBR5 depletion leads to accumulation of MYC in cells. We demonstrate interaction of UBR5 with MYC and reduced K48-linked ubiquitination of MYC upon loss of UBR5 in cells. Interestingly, in cancer cell lines with amplified MYC expression, depletion of UBR5 resulted in reduced cell survival, as a consequence of MYC stabilization. Finally, we show that MYC and UBR5 are co-amplified in more than 40% of cancer cells and that MYC copy number amplification correlates with enhanced transcriptional output of UBR5. This suggests that UBR5 acts as a buffer in MYC amplified settings and protects these cells from apoptosis.
- Published
- 2020
5. A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis
- Author
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Markus Wartmann, Josef Brüggen, Guido Bold, Marion Burglin, Arnaud Goepfert, Jürgen Mestan, Paul W. Manley, Jacqueline Loretan, Jeanette Marjorie Wood, Andreas Theuer, Georg Martiny-Baron, Peter Drückes, Peter R. Allegrini, Ursula Dürler, Paul M.J. McSheehy, Pascal Furet, Amanda Littlewood-Evans, Christian Schnell, Beatrice Bauer-Probst, and Robert Reuter
- Subjects
0301 basic medicine ,Models, Molecular ,Vascular Endothelial Growth Factor A ,Angiogenesis ,Melanoma, Experimental ,Angiogenesis Inhibitors ,CHO Cells ,Pharmacology ,Neovascularization ,Rats, Sprague-Dawley ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,0302 clinical medicine ,Cricetulus ,Cricetinae ,Drug Discovery ,medicine ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Phosphorylation ,Protein Kinase Inhibitors ,Cell Proliferation ,biology ,Neovascularization, Pathologic ,Cell growth ,Chemistry ,Kinase insert domain receptor ,biology.organism_classification ,Vascular Endothelial Growth Factor Receptor-2 ,Xenograft Model Antitumor Assays ,Rats ,Vascular endothelial growth factor A ,030104 developmental biology ,030220 oncology & carcinogenesis ,Molecular Medicine ,Female ,medicine.symptom ,Tyrosine kinase - Abstract
This paper describes the identification of 6-(pyrimidin-4-yloxy)-naphthalene-1-carboxamides as a new class of potent and selective human vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitors. In biochemical and cellular assays, the compounds exhibit single-digit nanomolar potency toward VEGFR2. Compounds of this series show good exposure in rodents when dosed orally. They potently inhibit VEGF-driven angiogenesis in a chamber model and rodent tumor models at daily doses of less than 3 mg/kg by targeting the tumor vasculature as demonstrated by ELISA for TIE-2 in lysates or by immunohistochemical analysis. This novel series of compounds shows a potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.
- Published
- 2015
6. Fibroblast Growth Factor Receptors as Novel Therapeutic Targets in SNF5-Deleted Malignant Rhabdoid Tumors
- Author
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Charles W. M. Roberts, Flavia Reimann, Simon Wöhrle, Audrey Kauffmann, Thomas Brümmendorf, Masato Murakami, Vito Guagnano, Andreas Weiss, Zainab Jagani, Astrid Pornon, Beatrice Bauer-Probst, Vincent Romanet, Christelle Stamm, Moriko Ito, William R. Sellers, Francesco Hofmann, Diana Graus Porta, and Anne Thuery
- Subjects
Carcinogenesis ,Chromosomal Proteins, Non-Histone ,lcsh:Medicine ,Biology ,Fibroblast growth factor ,medicine.disease_cause ,Chromatin remodeling ,Mice ,Cell Line, Tumor ,medicine ,Animals ,Humans ,SMARCB1 ,lcsh:Science ,Promoter Regions, Genetic ,Rhabdoid Tumor ,Cell Proliferation ,Multidisciplinary ,SWI/SNF complex ,lcsh:R ,HEK 293 cells ,SMARCB1 Protein ,Fibroblasts ,Chromatin Assembly and Disassembly ,Receptors, Fibroblast Growth Factor ,Molecular biology ,DNA-Binding Proteins ,HEK293 Cells ,Fibroblast growth factor receptor ,Cancer research ,lcsh:Q ,Signal transduction ,Research Article ,Signal Transduction ,Transcription Factors - Abstract
Malignant rhabdoid tumors (MRTs) are aggressive pediatric cancers arising in brain, kidney and soft tissues, which are characterized by loss of the tumor suppressor SNF5/SMARCB1. MRTs are poorly responsive to chemotherapy and thus a high unmet clinical need exists for novel therapies for MRT patients. SNF5 is a core subunit of the SWI/SNF chromatin remodeling complex which affects gene expression by nucleosome remodeling. Here, we report that loss of SNF5 function correlates with increased expression of fibroblast growth factor receptors (FGFRs) in MRT cell lines and primary tumors and that re-expression of SNF5 in MRT cells causes a marked repression of FGFR expression. Conversely, siRNA-mediated impairment of SWI/SNF function leads to elevated levels of FGFR2 in human fibroblasts. In vivo, treatment with NVP-BGJ398, a selective FGFR inhibitor, blocks progression of a murine MRT model. Hence, we identify FGFR signaling as an aberrantly activated oncogenic pathway in MRTs and propose pharmacological inhibition of FGFRs as a potential novel clinical therapy for MRTs.
- Published
- 2013
- Full Text
- View/download PDF
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