A5079607124- Protein Kinase Regulation and GTPase Signaling
- Protein Tyrosine Phosphatases
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Cell Adhesion Molecules Research
- Protein Structure and Dynamics
- RNA Research and Splicing
- Chronic Lymphocytic Leukemia Research
- Protein purification and stability
- Pancreatic and Hepatic Oncology Research
- Galectins and Cancer Biology
- Endoplasmic Reticulum Stress and Disease
- Biotin and Related Studies
- thermodynamics and calorimetric analyses
- Cardiac tumors and thrombi
- Cancer therapeutics and mechanisms
- Cellular Mechanics and Interactions
- Peptidase Inhibition and Analysis
- Acute Lymphoblastic Leukemia research
- Bone Tumor Diagnosis and Treatments
- RNA regulation and disease
- Viral Infectious Diseases and Gene Expression in Insects
University of Zurich
2020-2025
Over 100 co-crystal structures of KRAS switch-II pocket (SII-P) targeting inhibitors are currently available in the RCSB Protein Data Bank. These publicly invaluable tools that have led to a more in-depth understanding SII-P pocket, which is crucial for targeted drug design efforts. The binding modes (co-crystal structures) two KRAS(G12C) advanced clinical trials, GDC-6036 (divarasib) and LY3537982 (olomorasib), unavailable. Here, we reveal putative these G12C by utilizing structural data...
Thermal unfolding methods are commonly used as a predictive technique by tracking the protein's physical properties. Inherent protein thermal stability and profiles of biotherapeutics can help to screen or study potential drugs find stabilizing destabilizing conditions. Differential scanning calorimetry (DSC) is 'Gold Standard' for assays (TSA), but there also multitude other methodologies, such differential fluorimetry (DSF). The use an external probe increases assay throughput, making it...
Mutated KRAS proteins are frequently expressed in some of the most lethal human cancers, thus having been a target intensive drug discovery efforts for decades. Lately, KRAS(G12C) switch-II pocket (SII-P)-targeting covalent small molecule inhibitors have finally reached clinical practice. Sotorasib (AMG-510) was first FDA-approved inhibitor to treat KRAS(G12C)-positive non–small cell lung cancer (NSCLC), followed soon by adagrasib (MRTX849). Both drugs GDP-bound state KRAS(G12C), exploiting...
Abstract The protein K-Ras functions as a molecular switch in signaling pathways regulating cell growth. In the MAPK pathway, which is implicated many cancers, multiple proteins are thought to assemble at membrane with Ras-effector from Raf family. Here we propose an atomistic structural model for such assembly. Our starting point was asymmetric, GTP-mediated dimer model, generated using unbiased dynamics simulations and verified mutagenesis experiments. Adding further monomers head-to-tail...
Mutated KRAS proteins are frequently expressed in some of the most lethal human cancers and thus have been a target intensive drug discovery efforts for decades. Lately, KRAS(G12C) switch-II pocket (SII-P)-targeting covalent small molecule inhibitors finally reached clinical practice. Sotorasib (AMG-510) was first FDA-approved inhibitor to treat KRAS(G12C)-positive nonsmall cell lung cancer (NSCLC), followed soon by adagrasib (MRTX849). Both drugs GDP-bound state KRAS(G12C), exploiting...
Aberrant expression of the embryonal transcription factor TBXT (also known as brachyury) drives chordoma, a rare spinal neoplasm with no effective drug therapies. The gene network regulated by is poorly understood, and strategies to disrupt its abnormal activity for therapeutic purposes are lacking. Here, we developed TBXT-targeted designed ankyrin repeat proteins (T-DARPins) that selectively bind TBXT, inhibiting binding DNA expression. In chordoma cells, T-DARPins reduced cell cycle...
We have developed a method combining microinjection and automated fluorescence microscopy to continuously assess the degradation rate, subcellular localization intracellular concentration of protein analytes at single-cell level. Cells are unperturbed grown in unaltered environmental conditions show high viability. The injection defined ratios concentrations allows for clearly starting point degradation, without entanglement biosynthesis/uptake, often encountered existing methods....
Abstract The repeating failure of small molecules as specific inhibitors KRAS has drawn the attention to macromolecular structures, which can recognize their target with high affinity and specificity. Designed Ankyrin Repeat Proteins (DARPins) are multipurpose alternative reagents that have proved targets exceptional specificities selectivity often surpass those antibodies. Due additional outstanding ability act intracellularly within living cells recognition structural rather than linear...