A5058979231- PI3K/AKT/mTOR signaling in cancer
- Enzyme Structure and Function
- Virus-based gene therapy research
- Viral Infectious Diseases and Gene Expression in Insects
- RNA and protein synthesis mechanisms
- Cytokine Signaling Pathways and Interactions
- Viral Infections and Immunology Research
- Bacterial Genetics and Biotechnology
- RNA modifications and cancer
- Microfluidic and Bio-sensing Technologies
- Microfluidic and Capillary Electrophoresis Applications
- Plant Virus Research Studies
- Chronic Lymphocytic Leukemia Research
- Cancer Mechanisms and Therapy
- Melanoma and MAPK Pathways
- Quinazolinone synthesis and applications
- Renal and related cancers
- NF-κB Signaling Pathways
- Protein Kinase Regulation and GTPase Signaling
- Synthesis and biological activity
- Parvovirus B19 Infection Studies
- Ubiquitin and proteasome pathways
- RNA Research and Splicing
- Biotin and Related Studies
- Protein Tyrosine Phosphatases
Novartis (Switzerland)
2011-2024
Novartis Institutes for BioMedical Research
2011-2022
Center for Genomic Science
2015
Swiss Light Source
2009
Paul Scherrer Institute
2007-2009
Argonne National Laboratory
2008
Universität Hamburg
2008
Inserm
2008
École Polytechnique Fédérale de Lausanne
2004
ETH Zurich
2003
Radiation damage is the major impediment for obtaining structural information from biological samples by using ionizing radiation such as x-rays or electrons. The knowledge of underlying processes especially at cryogenic temperatures still fragmentary, and a consistent mechanism has not been found yet. By combination single-crystal x-ray diffraction, small-angle scattering, qualitative quantitative radiolysis experiments, we show that hydrogen gas, formed inside sample during irradiation,...
Bruton's tyrosine kinase (BTK), a cytoplasmic kinase, plays central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors limited to oncology indications based on their suboptimal selectivity. We describe the discovery preclinical profile LOU064 (remibrutinib, 25), potent, highly selective inhibitor. exhibits exquisite selectivity due binding inactive conformation has potential best-in-class inhibitor...
The predominant expression of phosphoinositide 3-kinase δ (PI3Kδ) in leukocytes and its critical role B T cell functions led to the hypothesis that selective inhibitors this isoform would have potential as therapeutics for treatment allergic inflammatory disease. Targeting specifically PI3Kδ should avoid side effects associated with ubiquitously expressed PI3Kα β isoforms. We disclose how morphing heterocyclic core previously discovered 4,6-diaryl quinazolines a significantly less lipophilic...
The discovery of inhibitors targeting novel allosteric kinase sites is very challenging. Such compounds, however, once identified could offer exquisite levels selectivity across the kinome. Herein we report our structure-based optimization strategy a dibenzodiazepine hit 1, discovered in fragment-based screen, yielding highly potent and selective PAK1 such as 2 3. Compound was cocrystallized with to confirm binding an site reveal key interactions. 3 modulated at cellular level due its...
Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using scaffold deconstruction–reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent isoform selective analogues with good pharmacokinetic properties. With compound 11, illustrate biochemical inhibition translates modulation isoform-dependent immune function (human, rat, mouse). After oral administration 11 rats, proximal PD markers are...
Abstract The transcription factor PAX8 is critical for the development of thyroid and urogenital system. Comprehensive genomic screens furthermore indicate an additional oncogenic role in renal ovarian cancers. While a plethora PAX8-regulated genes different contexts have been proposed, we still lack mechanistic understanding how engages molecular complexes to drive disease-relevant transcriptional programs. Here show that protein isoforms originating from MECOM locus form complex with PAX8....
Baculoviruses are ubiquitous insect viruses well known for their use as bioinsecticides, gene therapy vectors, and protein expression systems. Overexpression of recombinant proteins in cell culture utilizes the strong promoter polyhedrin gene. In infected larvae, forms robust intracellular crystals called polyhedra, which protect encased virions prolonged periods environment. Polyhedra produced by two unrelated families viruses, baculoviruses cypoviruses. The atomic structure cypovirus...
The gold standard for successful genome integration in Escherichia coli is the homologous recombination by bacteriophage-inspired lambda Red system. This method uses bacteriophage proteins to promote between a target DNA sequence and fragment, which introduced into bacterial cell electroporation. It allows researchers create specific genetic changes genomes, making it valuable tool studies microbiology biotechnology. However, this system not without limitations, are characteristic of its...
Radiation damage is one of the major impediments in obtaining high-resolution structural information utilizing ionizing radiation. From electron microscopy it known that irradiation biological samples results formation molecular hydrogen. In present work radiation-induced changes polypeptide cyclosporine A were observed at a temperature 100 K. Bond length are thought to be due hydrogen abstraction which chemically modifies molecules an irreversible way. The resulting might explain increase...
Macrophages are important cellular effectors in innate immune responses and play a major role autoimmune diseases such as rheumatoid arthritis. Cancer Osaka thyroid (COT) kinase, also known mitogen-activated protein kinase 8 (MAP3K8) tumor progression locus 2 (Tpl-2), is serine-threonine (ST) key regulator the production of pro-inflammatory cytokines macrophages. Due to its pivotal biology, COT has been identified an attractive target for pharmaceutical research that directed at discovery...
Cancer Osaka thyroid (COT) kinase is an important regulator of pro-inflammatory cytokines in macrophages. Thus, pharmacologic inhibition COT should be a valid approach to therapeutically intervene the pathogenesis macrophage-driven inflammatory diseases such as rheumatoid arthritis. We report discovery and chemical optimization novel series inhibitors, with unprecedented nanomolar potency for TNFα. Pharmacological profiling vivo revealed high metabolism these compounds rats which was...
Bruton's tyrosine kinase (BTK) is a member of the TEC family and selectively expressed in subset immune cells. It key regulator antigen receptor signaling B cells Fc mast macrophages. A BTK inhibitor will likely have positive impact on autoimmune diseases which are caused by autoreactive immune-complex driven inflammation. We report design, optimization, characterization potent selective covalent inhibitors. Starting from reversible 3 binding to an inactive conformation BTK, we designed...
Balanced pan-class I phosphoinositide 3-kinase inhibition as an approach to cancer treatment offers the prospect of treating a broad range tumor types and/or way achieve greater efficacy with single inhibitor. Taking buparlisib starting point, balanced PI3K inhibitor 40 (NVP-CLR457) was identified what considered be best-in-class profile. Key optimization this profile eliminating microtubule stabilizing off-target activity, balancing profile, minimizing CNS penetration, and developing...
In order to perform X-ray crystallographic analysis, protein crystals are removed from their growing solution by means of a nylon loop, which is then mounted on goniometer. As this process repeated for large number crystals, there need automation, especially with regard the placement loop. A novel technique involving use acoustic radiation forces and micro-machined fluidic device introduced here. After insertion into channel, positioned in row along its centre-line excitation high-frequency...
Summary BTB and CNC homolog 1 (BACH1) is a master transcriptional regulator of the cellular oxidative stress response pro-metastatic oncogene. Post-translational stability BACH1 tightly regulated by distinct F-box ubiquitin ligases, including SCF FBXO22 FBXL17 . However, molecular details have been elusive. Here, we reveal structural switch in that controls recognition three-dimensional degron domain, thus explaining its specificity for dimeric BACH1. We describe how cancer-associated...
Harnessing autophagy for targeted degradation is a promising extension to proteasome-based 18 protein because of the capacity and versatility lysosomes degrade large 19 complex cargo, thus broadening scope therapeutic targets. While small-molecule degraders 20 recruiting machinery targets are starting emerge, it remains unclear which component 21 lysosomal pathway most efficacious induce selective target degradation. Here, we 22 describe two orthogonal induced-proximity strategies identify...
Poster Sessions independent P8 molecules are superimposed on one of the P3 corecapsid protein.Cα trace molecule is shown in a stick model.Start and end two induced-fit loops, gray stick, indicated terms residue number.