A5068763614- Melanoma and MAPK Pathways
- Synthesis and biological activity
- Asymmetric Synthesis and Catalysis
- Chemical Synthesis and Reactions
- NF-κB Signaling Pathways
- Organoboron and organosilicon chemistry
- Beetle Biology and Toxicology Studies
- Phytochemical compounds biological activities
- Asymmetric Hydrogenation and Catalysis
- Cell death mechanisms and regulation
- Crystallization and Solubility Studies
- Sulfur-Based Synthesis Techniques
- Synthetic Organic Chemistry Methods
- Chemical Synthesis and Analysis
- X-ray Diffraction in Crystallography
- Immune Response and Inflammation
- Enzyme function and inhibition
- Protein Kinase Regulation and GTPase Signaling
- Quinazolinone synthesis and applications
- Coleoptera Taxonomy and Distribution
- Cytokine Signaling Pathways and Interactions
- Advanced Synthetic Organic Chemistry
- Cancer-related Molecular Pathways
- Click Chemistry and Applications
- interferon and immune responses
Novartis (Switzerland)
2008-2024
Novartis Institutes for BioMedical Research
2007-2021
Philipps University of Marburg
1990-2002
University of Cambridge
1994-1995
University of Milan
1994
The propagation of the hepatitis C virus (HCV) is a complex process that requires both host and viral proteins. To facilitate identification cell factors are required for HCV replication, we screened panel small interference RNAs preferentially target human protein kinases using an replicon expressing firefly luciferase gene as genetic reporter. Small specific three kinases, Csk, Jak1, Vrk1, were identified reproducibly reduce RNA levels in replicon-bearing cells. Treatment cells with...
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is essential for immune responses triggered by antigen receptors but the contribution of its paracaspase activity not fully understood. Here, we studied how MALT1 proteolytic function regulates T-cell activation and fate after engagement receptor pathway. We show that MLT-827, a potent selective inhibitor, does prevent initial phase activation, in contrast to pan-protein kinase C inhibitor AEB071. However, MLT-827...
Abstract
Genetic disruption or short-term pharmacological inhibition of MALT1 protease is effective in several preclinical models autoimmunity and B cell malignancies. Despite these protective effects, the severe reduction regulatory T cells (Tregs) associated IPEX-like pathology occurring upon congenital mice has raised concerns about long-term safety inhibition. Here we describe results a series toxicology studies rat dog species using MLT-943, novel potent selective inhibitor. While MLT-943...
Enone 3, an advanced C9-C24 subunit of discodermolide, was synthesised in 17 steps starting from the ethyl ketone (R)-4. The sequence 19 → 23 developed to introduce Z-alkene at C13, enabling conversion 3 into complete segment 5.
G-protein-coupled receptor SUCNR1 (succinate 1 or GPR91) senses the citric cycle intermediate succinate and is implicated in various pathological conditions such as rheumatoid arthritis, liver fibrosis, obesity. Here, we describe a novel antagonist scaffold discovered by high-throughput screening. The poor permeation absorption properties of most potent compounds, which were zwitterionic nature, could be improved formation an internal salt bridge, helped shielding two opposite charges thus...
The paracaspase MALT1 has gained increasing interest as a target for the treatment of subsets lymphomas well autoimmune diseases, and there is need suitable compounds to explore therapeutic potential this target. Here, we report optimization in vivo potency pyrazolopyrimidines, class highly selective allosteric inhibitors. High doses initial lead compound led tumor stasis an activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) xenograft model, but suffered from short half-life...
MALT1 plays a central role in immune cell activation by transducing NF-κB signaling, and its proteolytic activity represents key node for therapeutic intervention. Two cycles of scaffold morphing high-throughput biochemical screening hit resulted the discovery MLT-231, which enabled successful pharmacological validation allosteric inhibition preclinical models humoral responses B-cell lymphomas. Herein, we report structural relationships (SARs) analysis physicochemical properties...
Hdm2 (human MDM2, human double minute 2 homologue) counteracts p53 function by direct binding to and ubiquitin-dependent protein degradation. Activation of inhibitors the p53-Hdm2 interaction is being pursued as a therapeutic strategy in wild-type cancers. In addition, HdmX MDMX, MDM4) was also identified an important target efficiently reactivate p53, it likely that dual inhibition beneficial. Herein we report four new X-ray structures for five complexes, involving different classes...
IL-17, a pro-inflammatory cytokine produced mainly by Th17 cells, is involved in the immune response to fungal and bacterial infections, whereas its aberrant production associated with autoimmune inflammatory diseases. IL-17 blocking antibodies like secukinumab (Cosentyx) have been developed are used treat conditions psoriasis, psoriatic arthritis, ankylosing spondylitis. Recently, low molecular weight inhibitor LY3509754 entered clinic but was discontinued Phase 1 due adverse effects. In...
MAP-activated protein kinase 2 (MK2) plays an important role in the regulation of innate immune response as well cell survival upon DNA damage. Despite its potential for treatment inflammation and cancer, to date no MK2 low molecular weight inhibitors have reached clinic, mainly due inadequate absorption, distribution, metabolism, excretion (ADME) properties. We describe here approach based on specifically placed fluorine within a recently described pyrrole-based inhibitor scaffold...