Ralph Mazitschek
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View article: Prolyl-tRNA synthetase inhibition disrupts oncogenic translation in T-cell acute lymphoblastic leukemia
Prolyl-tRNA synthetase inhibition disrupts oncogenic translation in T-cell acute lymphoblastic leukemia Open
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer marked by the abnormal growth of immature thymocytes. 5-year survival rate in T-ALL is about 85% in children and less than 50% in adults. Relapsed/refractory T-ALL r…
View article: Proximity-induced rewiring of oncogenic kinase triggers apoptosis
Proximity-induced rewiring of oncogenic kinase triggers apoptosis Open
The active site’s electric field is integral to enzymatic catalysis (e.g., substrate recognition) and nature employs charge-altering post-translational modifications (e.g., phosphorylation) to perturb this electric field and regulate enzym…
View article: A Time‐Resolved Förster Resonance Energy Transfer Platform for the Facile Quantification of Small Molecule Drugs in Cell Lysate
A Time‐Resolved Förster Resonance Energy Transfer Platform for the Facile Quantification of Small Molecule Drugs in Cell Lysate Open
Many pharmacologically relevant drug targets are located inside cells, requiring small‐molecule therapeutics to penetrate the plasma membrane faster than they are metabolically inactivated or expelled by efflux pumps. Accurate measurement …
View article: GluProRS Inhibition Abolishes Cancer Stem Cells in Pancreatic Cancer by Inducing the Integrated Stress Response and Countering TGFβ/Activin-SMAD2/3-HIF1A
GluProRS Inhibition Abolishes Cancer Stem Cells in Pancreatic Cancer by Inducing the Integrated Stress Response and Countering TGFβ/Activin-SMAD2/3-HIF1A Open
The developmentally dynamic stem cell-like subpopulation in cancers known as cancer stem cells (CSCs) metastasize efficiently, form new tumours, and are resistant to current therapeutics. Understanding the molecular mechanisms of the stem …
View article: A method for the detection and enrichment of endogenous cereblon substrates
A method for the detection and enrichment of endogenous cereblon substrates Open
C-Terminal cyclic imides are posttranslational modifications on proteins that are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN). Despite the observation of these modifications across the proteome by mass spectro…
View article: Converging mechanism of UM171 and KBTBD4 neomorphic cancer mutations
Converging mechanism of UM171 and KBTBD4 neomorphic cancer mutations Open
View article: UM171 glues asymmetric CRL3–HDAC1/2 assembly to degrade CoREST corepressors
UM171 glues asymmetric CRL3–HDAC1/2 assembly to degrade CoREST corepressors Open
View article: Loss of P. falciparum Amino Acid Transporter (ApiAT2) Increases Intracellular Proline and Confers Resistance to Prolyl-tRNA Synthetase Inhibitors
Loss of P. falciparum Amino Acid Transporter (ApiAT2) Increases Intracellular Proline and Confers Resistance to Prolyl-tRNA Synthetase Inhibitors Open
View article: The contribution of cyclic imide stereoisomers on cereblon-dependent activity
The contribution of cyclic imide stereoisomers on cereblon-dependent activity Open
A systematic investigation of cyclic imide stereoisomers in small molecules, peptides, and proteins, examining their racemization, CRBN engagement, ternary complex formation in vitro , and resulting degradation outcomes in cells.
View article: Identification of a Polypeptide Inhibitor of <i>O</i>-GlcNAc Transferase with Picomolar Affinity
Identification of a Polypeptide Inhibitor of <i>O</i>-GlcNAc Transferase with Picomolar Affinity Open
O-GlcNAc transferase (OGT) is an essential mammalian enzyme that binds thousands of different proteins, including substrates that it glycosylates and nonsubstrate interactors that regulate its biology. OGT also has one proteolytic s…
View article: Protocol for the comprehensive biochemical and cellular profiling of small-molecule degraders using CoraFluor TR-FRET technology
Protocol for the comprehensive biochemical and cellular profiling of small-molecule degraders using CoraFluor TR-FRET technology Open
View article: Spatial Profiling of Metals through Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging
Spatial Profiling of Metals through Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging Open
The spatial-omic analysis of biomolecules such as nucleic acids, lipids, metabolites, and proteins is advancing the study of biological systems and processes in a physio-pathological context. Here, we describe an innovative matrix-assisted…
View article: KBTBD4 Cancer Hotspot Mutations Drive Neomorphic Degradation of HDAC1/2 Corepressor Complexes
KBTBD4 Cancer Hotspot Mutations Drive Neomorphic Degradation of HDAC1/2 Corepressor Complexes Open
Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function 1 . As a substrate receptor of the CULLIN3-RBX1 E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma (MB) 2 , the most …
View article: Asymmetric Engagement of Dimeric CRL3<sup>KBTBD4</sup>by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes
Asymmetric Engagement of Dimeric CRL3<sup>KBTBD4</sup>by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes Open
UM171 is a potent small molecule agonist of ex vivo human hematopoietic stem cell (HSC) self-renewal, a process that is tightly controlled by epigenetic regulation. By co-opting KBTBD4, a substrate receptor of the CULLIN3-RING E3 ubiquitin…
View article: Epigenetic modulation through BET bromodomain inhibitors as a novel therapeutic strategy for progranulin-deficient frontotemporal dementia
Epigenetic modulation through BET bromodomain inhibitors as a novel therapeutic strategy for progranulin-deficient frontotemporal dementia Open
View article: Author Correction: Oxycodone withdrawal induces HDAC1/HDAC2-dependent transcriptional maladaptations in the reward pathway in a mouse model of peripheral nerve injury
Author Correction: Oxycodone withdrawal induces HDAC1/HDAC2-dependent transcriptional maladaptations in the reward pathway in a mouse model of peripheral nerve injury Open
View article: Inhibiting the Keap1/Nrf2 Protein‐Protein Interaction with Protein‐Like Polymers
Inhibiting the Keap1/Nrf2 Protein‐Protein Interaction with Protein‐Like Polymers Open
Successful and selective inhibition of the cytosolic protein‐protein interaction (PPI) between nuclear factor erythroid 2‐related factor 2 (Nrf2) and Kelch‐like ECH‐associating protein 1 (Keap1) can enhance the antioxidant response, with t…
View article: A lysate-based TR-FRET approach for the facile quantification of cellular drug concentration
A lysate-based TR-FRET approach for the facile quantification of cellular drug concentration Open
Many pharmacologically relevant drug targets are located inside cells. The development of therapeutically active small molecule modulators for intracellular targets requires that successful drug candidates can efficiently pass through the …
View article: A randomized, double-blind, placebo-controlled study of histone deacetylase type 6 inhibition for the treatment of painful diabetic peripheral neuropathy
A randomized, double-blind, placebo-controlled study of histone deacetylase type 6 inhibition for the treatment of painful diabetic peripheral neuropathy Open
Introduction: Current treatments for painful diabetic peripheral neuropathy (DPN) are insufficiently effective for many individuals and do not treat nonpain signs and symptoms. The enzyme histone deacetylase type 6 (HDAC6) may play a role …
View article: Diverse evolutionary pathways challenge the use of collateral sensitivity as a strategy to suppress resistance
Diverse evolutionary pathways challenge the use of collateral sensitivity as a strategy to suppress resistance Open
Drug resistance remains a major obstacle to malaria control and eradication efforts, necessitating the development of novel therapeutic strategies to treat this disease. Drug combinations based on collateral sensitivity, wherein resistance…
View article: Author response: Diverse evolutionary pathways challenge the use of collateral sensitivity as a strategy to suppress resistance
Author response: Diverse evolutionary pathways challenge the use of collateral sensitivity as a strategy to suppress resistance Open
Full text Figures and data Side by side Abstract Editor's evaluation eLife digest Introduction Results Discussion Methods Appendix 1 Data availability References Decision letter Author response Article and author information Metrics Abstra…
View article: Oxycodone withdrawal induces HDAC1/HDAC2-dependent transcriptional maladaptations in the reward pathway in a mouse model of peripheral nerve injury
Oxycodone withdrawal induces HDAC1/HDAC2-dependent transcriptional maladaptations in the reward pathway in a mouse model of peripheral nerve injury Open
View article: Advances in malaria pharmacology and the online guide to MALARIA PHARMACOLOGY: IUPHAR review 38
Advances in malaria pharmacology and the online guide to MALARIA PHARMACOLOGY: IUPHAR review 38 Open
Antimalarial drug discovery has until recently been driven by high‐throughput phenotypic cellular screening, allowing millions of compounds to be assayed and delivering clinical drug candidates. In this review, we will focus on target‐base…
View article: Structural and biochemical characterization establishes a detailed understanding of KEAP1-CUL3 complex assembly
Structural and biochemical characterization establishes a detailed understanding of KEAP1-CUL3 complex assembly Open
KEAP1 promotes the ubiquitin-dependent degradation of NRF2 by assembling into a CUL3-dependent ubiquitin ligase complex. Oxidative and electrophilic stress inhibit KEAP1 allowing NRF2 to accumulate for the transactivation of stress respons…
View article: The Cyclimids: Degron-inspired cereblon binders for targeted protein degradation
The Cyclimids: Degron-inspired cereblon binders for targeted protein degradation Open
Cereblon (CRBN) is an E3 ligase substrate adapter widely exploited for targeted protein degradation (TPD) strategies. However, achieving efficient and selective target degradation is a preeminent challenge with ligands that engage CRBN. He…
View article: Data from Ubiquitin Proteasome System Stress Underlies Synergistic Killing of Ovarian Cancer Cells by Bortezomib and a Novel HDAC6 Inhibitor
Data from Ubiquitin Proteasome System Stress Underlies Synergistic Killing of Ovarian Cancer Cells by Bortezomib and a Novel HDAC6 Inhibitor Open
Purpose: Elevated metabolic activity of ovarian cancer cells causes increased ubiquitin-proteasome-system (UPS) stress, resulting in their greater sensitivity to the toxic effects of proteasomal inhibition. The proteasomes and a pot…
View article: Data from Ubiquitin Proteasome System Stress Underlies Synergistic Killing of Ovarian Cancer Cells by Bortezomib and a Novel HDAC6 Inhibitor
Data from Ubiquitin Proteasome System Stress Underlies Synergistic Killing of Ovarian Cancer Cells by Bortezomib and a Novel HDAC6 Inhibitor Open
Purpose: Elevated metabolic activity of ovarian cancer cells causes increased ubiquitin-proteasome-system (UPS) stress, resulting in their greater sensitivity to the toxic effects of proteasomal inhibition. The proteasomes and a pot…
View article: Supplementary Figures S1-S4 from Ubiquitin Proteasome System Stress Underlies Synergistic Killing of Ovarian Cancer Cells by Bortezomib and a Novel HDAC6 Inhibitor
Supplementary Figures S1-S4 from Ubiquitin Proteasome System Stress Underlies Synergistic Killing of Ovarian Cancer Cells by Bortezomib and a Novel HDAC6 Inhibitor Open
Supplementary Figures S1-S4 from Ubiquitin Proteasome System Stress Underlies Synergistic Killing of Ovarian Cancer Cells by Bortezomib and a Novel HDAC6 Inhibitor
View article: Supplementary Figures S1-S4 from Ubiquitin Proteasome System Stress Underlies Synergistic Killing of Ovarian Cancer Cells by Bortezomib and a Novel HDAC6 Inhibitor
Supplementary Figures S1-S4 from Ubiquitin Proteasome System Stress Underlies Synergistic Killing of Ovarian Cancer Cells by Bortezomib and a Novel HDAC6 Inhibitor Open
Supplementary Figures S1-S4 from Ubiquitin Proteasome System Stress Underlies Synergistic Killing of Ovarian Cancer Cells by Bortezomib and a Novel HDAC6 Inhibitor
View article: Diagnostic TR-FRET assays for detection of antibodies in patient samples
Diagnostic TR-FRET assays for detection of antibodies in patient samples Open
Serological assays are important diagnostic tools for surveying exposure to the pathogen, monitoring immune response post vaccination, and managing spread of the infectious agent among the population. Current serological laboratory assays …