Sonja Sievers
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View article: Design, Synthesis, and Structural Evolution of Pseudo‐Natural Product IDO1 Inhibitors and Degraders
Design, Synthesis, and Structural Evolution of Pseudo‐Natural Product IDO1 Inhibitors and Degraders Open
Terpenoid alkaloids are derived from the fusion of structurally diverse terpenoid‐ and alkaloid moieties. The biologically relevant chemical space defined by this unique natural product (NP) class may be explored beyond the limitations of …
View article: Design, Synthesis, and Structural Evolution of Pseudo‐Natural Product IDO1 Inhibitors and Degraders
Design, Synthesis, and Structural Evolution of Pseudo‐Natural Product IDO1 Inhibitors and Degraders Open
Terpenoid alkaloids are derived from the fusion of structurally diverse terpenoid‐ and alkaloid moieties. The biologically relevant chemical space defined by this unique natural product (NP) class may be explored beyond the limitations of …
View article: Pseudo‐Natural Products Inspired by Aspidospermidine‐, Strychnos‐, and Koumine Monoterpene Indole Alkaloids Reveal Pyrimidine Biosynthesis Inhibitors
Pseudo‐Natural Products Inspired by Aspidospermidine‐, Strychnos‐, and Koumine Monoterpene Indole Alkaloids Reveal Pyrimidine Biosynthesis Inhibitors Open
In pseudo‐natural product (PNP) design, natural product fragments are combined in arrangements not found in nature to afford novel biologically relevant NP‐related compound classes. A pseudo‐natural product compound collection inspired by …
View article: An Indole Dearomatization Strategy for the Synthesis of Pseudo‐Natural Products
An Indole Dearomatization Strategy for the Synthesis of Pseudo‐Natural Products Open
The indole moiety is a privileged fragment that frequently populates existing bioactive compound collections. The development of an indole‐dearomatization sequence and its application for library expansion of a collection of indole‐contain…
View article: Identification of Natural Killer Cell Enhancers Through Mimicking of the Tumor Microenvironment
Identification of Natural Killer Cell Enhancers Through Mimicking of the Tumor Microenvironment Open
The tumor microenvironment (TME) is a pro‐cancerous niche harboring immunosuppressive factors that are secreted by cancer cells and the surrounding cancer‐supportive tissue, such as kynurenine, prostaglandin E2 and transforming growth fact…
View article: Phenylpyrazoles as Inhibitors of the m<sup>6</sup>A RNA-Binding Protein YTHDF2
Phenylpyrazoles as Inhibitors of the m<sup>6</sup>A RNA-Binding Protein YTHDF2 Open
The N6-methyladenosine (m6A) modification, which is the most common RNA modification in eukaryotes, is regulated by the "writer" methyltransferases, the "reader" m6A binding proteins, and the "eraser" demethylases. m6A plays a multifunctio…
View article: Phenotype-directed discovery of diverse, biologically-relevant molecular scaffolds
Phenotype-directed discovery of diverse, biologically-relevant molecular scaffolds Open
An array of reactions of diazo substrates with many possible outcomes was executed, and the biological relevance of the resulting products assessed in the cell painting assay.
View article: Identification of 5-amino-1,3,4-thiadiazole appended isatins as bioactive small molecules with polypharmacological activities
Identification of 5-amino-1,3,4-thiadiazole appended isatins as bioactive small molecules with polypharmacological activities Open
A series of new 5-amino-1,3,4-thiadiazole appended isatins induced significant cellular morphological changes and showed high biological profiling similarities to an antifungal agent and a chemokine receptor inhibitor.
View article: Phenomics‐Based Discovery of Novel Orthosteric Choline Kinase Inhibitors
Phenomics‐Based Discovery of Novel Orthosteric Choline Kinase Inhibitors Open
Choline kinase alpha (CHKA) is a central mediator of cell metabolism linked to cancer and immune regulation. Cellular and clinical evaluation of CHKA has been hampered by challenges in the development of drug‐like choline kinase inhibitors…
View article: LIN28‐Targeting Chromenopyrazoles and Tetrahydroquinolines Induced Cellular Morphological Changes and Showed High Biosimilarity with BRD PROTACs
LIN28‐Targeting Chromenopyrazoles and Tetrahydroquinolines Induced Cellular Morphological Changes and Showed High Biosimilarity with BRD PROTACs Open
The probing of small molecules with heterocyclic scaffolds covering unexplored chemical space and the evaluation of their biological relevance are essential parts of forward chemical genetics approaches and for the development of potential…
View article: Detection of a Mitochondrial Fragmentation and Integrated Stress Response Using the Cell Painting Assay
Detection of a Mitochondrial Fragmentation and Integrated Stress Response Using the Cell Painting Assay Open
Mitochondria are cellular powerhouses and are crucial for cell function. However, they are vulnerable to internal and external perturbagens that may impair mitochondrial function and eventually lead to cell death. In particular, small mole…
View article: Identification of a Monovalent Pseudo-Natural Product Degrader Class Supercharging Degradation of IDO1 by its native E3 KLHDC3
Identification of a Monovalent Pseudo-Natural Product Degrader Class Supercharging Degradation of IDO1 by its native E3 KLHDC3 Open
Targeted protein degradation (TPD) modulates protein function beyond inhibition of enzyme activity or protein-protein interactions. Most degrader drugs function by directly mediating proximity between a neosubstrate and hijacked E3 ligase.…
View article: Profiling Cellular Morphological Changes Induced by Dual‐Targeting PROTACs of Aurora Kinase and RNA‐Binding Protein YTHDF2
Profiling Cellular Morphological Changes Induced by Dual‐Targeting PROTACs of Aurora Kinase and RNA‐Binding Protein YTHDF2 Open
Proteolysis targeting chimeras (PROTACs) are new chemical modalities that degrade proteins of interest, including established kinase targets and emerging RNA‐binding proteins (RBPs). Whereas diverse sets of biochemical, biophysical and cel…
View article: The Pseudo‐Natural Product Tafbromin Selectively Targets the TAF1 Bromodomain 2
The Pseudo‐Natural Product Tafbromin Selectively Targets the TAF1 Bromodomain 2 Open
Phenotypic assays detect small‐molecule bioactivity at functionally relevant cellular sites, and inherently cover a variety of targets and mechanisms of action. They can uncover new small molecule‐target pairs and may give rise to novel bi…
View article: Illuminating Dark Chemical Matter Using the Cell Painting Assay
Illuminating Dark Chemical Matter Using the Cell Painting Assay Open
Screening for small-molecule modulators of disease-relevant targets and phenotypes is the first step on the way to new drugs. Large compound libraries have been synthesized by academia and, particularly, pharmaceutical companies to meet th…
View article: Discovery of a Novel Pseudo‐Natural Product Aurora Kinase Inhibitor Chemotype through Morphological Profiling
Discovery of a Novel Pseudo‐Natural Product Aurora Kinase Inhibitor Chemotype through Morphological Profiling Open
The pseudo‐natural product (pseudo‐NP) concept aims to combine NP fragments in arrangements that are not accessible through known biosynthetic pathways. The resulting compounds retain the biological relevance of NPs but are not yet linked …
View article: Discovery of the sEH Inhibitor Epoxykynin as a Potent Kynurenine Pathway Modulator
Discovery of the sEH Inhibitor Epoxykynin as a Potent Kynurenine Pathway Modulator Open
Disease-related phenotypic assays enable unbiased discovery of novel bioactive small molecules and may provide novel insights into physiological systems and unprecedented molecular modes of action (MMOA). Herein, we report the identificati…
View article: Assessing biologic/toxicologic effects of extractables from plastic contact materials for advanced therapy manufacturing using cell painting assay and cytotoxicity screening
Assessing biologic/toxicologic effects of extractables from plastic contact materials for advanced therapy manufacturing using cell painting assay and cytotoxicity screening Open
Plastic components are essential in the pharmaceutical industry, encompassing container closure systems, laboratory handling equipment, and single-use systems. As part of their material qualification process, studies on interactions betwee…
View article: Fluorescent probes and degraders of the sterol transport protein Aster-A
Fluorescent probes and degraders of the sterol transport protein Aster-A Open
Our understanding of sterol transport proteins (STPs) has increased exponentially in the last decades with advances in the cellular and structural biology of these important proteins. However, small molecule probes have only recently been …
View article: KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape
KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape Open
PURPOSE Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary KIT mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have c…
View article: Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA
Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA Open
Avapritinib is the only potent and selective inhibitor approved for the treatment of D842V-mutant gastrointestinal stromal tumors (GIST), the most common primary mutation of the platelet-derived growth factor receptor α (PDGFRA). The appro…
View article: CCDC 2217208: Experimental Crystal Structure Determination
CCDC 2217208: Experimental Crystal Structure Determination Open
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available …
View article: CCDC 2217135: Experimental Crystal Structure Determination
CCDC 2217135: Experimental Crystal Structure Determination Open
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available …
View article: CCDC 2217134: Experimental Crystal Structure Determination
CCDC 2217134: Experimental Crystal Structure Determination Open
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available …
View article: Discovery of a novel pseudo-natural product Aurora kinase inhibitor chemotype through morphological profiling
Discovery of a novel pseudo-natural product Aurora kinase inhibitor chemotype through morphological profiling Open
The pseudo-natural product (pseudo-NP) concept aims to combine NP fragments in arrangements that are not accessible through known biosynthetic pathways. The resulting compounds retain the biological relevance of NPs but are not yet linked …
View article: Discovery of the sEH Inhibitor Epoxykynin as Potent Kynurenine Pathway Modulator
Discovery of the sEH Inhibitor Epoxykynin as Potent Kynurenine Pathway Modulator Open
Disease-related phenotypic assays enable unbiased discovery of novel bioactive small molecules and may provide novel insights into physiological systems and unprecedented molecular modes-of-action (MMOA). Herein we report the identificatio…
View article: Detection of a Mitochondrial Stress Phenotype using the Cell Painting Assay
Detection of a Mitochondrial Stress Phenotype using the Cell Painting Assay Open
Mitochondria are cellular powerhouses and crucial for cell function. However, these organelles are vulnerable to internal and external perturbagens that may impair mitochondrial function and eventually lead to cell death. In particular, sm…
View article: Inducin Triggers LC3‐Lipidation and ESCRT‐Mediated Lysosomal Membrane Repair
Inducin Triggers LC3‐Lipidation and ESCRT‐Mediated Lysosomal Membrane Repair Open
Lipidation of the LC3 protein has frequently been employed as a marker of autophagy. However, LC3‐lipidation is also triggered by stimuli not related to canonical autophagy. Therefore, characterization of the driving parameters for LC3 lip…