A5030231306- Cancer-related Molecular Pathways
- Click Chemistry and Applications
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- Cancer Genomics and Diagnostics
- Advanced biosensing and bioanalysis techniques
- Epigenetics and DNA Methylation
- Microtubule and mitosis dynamics
- Antibiotic Resistance in Bacteria
- Peptidase Inhibition and Analysis
- Protein Degradation and Inhibitors
- MicroRNA in disease regulation
- Hemoglobin structure and function
- Chemical Synthesis and Analysis
- Renal and related cancers
- Molecular Biology Techniques and Applications
- HIV/AIDS drug development and treatment
- Enzyme-mediated dye degradation
- Trypanosoma species research and implications
- Complement system in diseases
- Multiple Myeloma Research and Treatments
- Pharmaceutical and Antibiotic Environmental Impacts
- Synthesis and Reactivity of Heterocycles
- Cystic Fibrosis Research Advances
- Synthesis and Characterization of Heterocyclic Compounds
Novartis (Switzerland)
2012-2024
Novartis Institutes for BioMedical Research
2012-2024
Centre National de la Recherche Scientifique
1996
Targeted protein degradation (TPD) mediates level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only few have been utilized TPD. Interestingly, the workhorse ligase CRBN observed be downregulated settings resistance immunomodulatory inhibitory drugs (IMiDs). Here we show that essential receptor DCAF1 can harnessed utilizing selective,...
As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as clinical candidate is currently phase 1 development. This article provides overview discovery this new inhibitor. The following aspects are addressed: mechanism action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic pharmacodynamic properties,...
BackgroundNXL104 is a novel-structure β-lactamase inhibitor with potent activity against both class A and C enzymes. Among the carbapenemases, KPC-type enzymes are now spreading rapidly KPC-related carbapenemase resistance an emerging phenomenon of great clinical importance. The NXL104 KPC β-lactamases was examined.
NXL104 is a potent inhibitor of class A and C serine β-lactamases, including KPC carbapenemases. Native NXL104-inhibited TEM-1 P99 β-lactamases analyzed by liquid chromatography-electrospray ionization-time flight mass spectrometry revealed that the inactivated enzymes formed covalent adduct with NXL104. The principal inhibitory characteristics against were determined, partition ratios, dissociation constants (K), rate for deactivation (k(2)), reactivation rates. P99, characterized high...
In this study, we describe the rapid identification of potent binders for WD40 repeat domain (WDR) DCAF1. This was achieved by two rounds iterative focused screening a small set compounds selected on basis internal WDR knowledge followed hit expansion. Subsequent structure-based design led to nanomolar potency with clear exit vector enabling DCAF1-based bifunctional degrader exploration.
ABSTRACT NXL101 is one of a new class quinoline antibacterial DNA gyrase and topoisomerase IV inhibitors showing potent activity against gram-positive bacteria, including methicillin- fluoroquinolone-resistant strains. inhibited more effectively than from Escherichia coli , whereas the converse true enzymes Staphylococcus aureus . This apparent target preference opposite to that which associated with most fluoroquinolone antibiotics. In vitro isolation S. mutants resistant followed by...
Biomarkers for patient selection are essential the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report discovery a novel strategy p53–HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, have identified gene expression signature consisting 13 up-regulated genes that predicts to NVP-CGM097 both lines patient-derived tumor xenograft models....
Abstract Activation of p53 by inhibitors the p53–MDM2 interaction is being pursued as a therapeutic strategy in wild-type cancers. Here, we report distinct mechanisms which novel, potent, and selective inhibitor HDM201 elicits efficacy when applied at various doses schedules. Continuous exposure led to induction p21 delayed accumulation apoptotic cells. By comparison, high-dose pulses were associated with marked PUMA rapid onset apoptosis. shRNA screens identified mediator response...
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....
We have developed a novel assay specific to MraY, which catalyzes the first membrane step in biosynthesis of bacterial cell wall peptidoglycan. This was accomplished by using UDP-MurNAc-N(epsilon)-dansylpentapeptide, fluorescent derivative MraY nucleotide substrate, and partially purified preparation solubilized from membranes an Escherichia coli overproducing strain. Two versions were developed, one consisting high-pressure liquid chromatography separation substrate product (dansylated...
Abstract FAP (Fibroblast Activation Protein) is expressed on cancer-associated fibroblasts (CAFs) and a highly attractive target in Radioligand Therapy (RLT) due to its pan cancer potential. The penetrating nature of β radiation hypothesized drive ‘cross-fire effect’ from CAFs tumor cells resulting DNA damage cell death. Known targeting ligands show excellent selective uptake the clinic but suffer short retention which limits their application as therapeutic modality. Herein we describe...
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...
Abstract To study the behavior of MDM2‐p53 inhibitors in a disease‐relevant cellular model, we have developed and validated set bioorthogonal probes that can be fluorescently labeled cells used high‐content screening assays. By using automated image analysis with single‐cell resolution, could visualize intracellular target binding compounds by co‐localization quantify upregulation upon inhibition an osteosarcoma model. Additionally, high‐throughput assay to occupancy non‐tagged competition...
Mouse double minute 2 homolog (MDM2, Hdm2) is an important negative regulator of the tumor suppressor p53. Using a mRNA based display technique to screen library >1012in vitro-translated cyclic peptides, we have identified macrocyclic ligand that shows picomolar potency on MDM2. X-Ray crystallography reveals novel binding mode utilizing unique pharmacophore occupy Phe/Trp/Leu pockets Conjugation cell-penetrating peptide (cCPP) initially non cell-permeable enables cellular uptake and...
Background and Purpose Helix stapling enhances the activity of peptides that interact with a target protein in helical conformation. These staples are also supposed to change pharmacokinetics molecules promote cytoplasmic targeting. We assessed extent which pharmacokinetic characteristics function staple for peptide inhibiting interaction p53 human double minute 2 (Hdm2) differ from those standard cationic cell‐penetrating nona‐arginine. Experimental Approach Stapled linear counterparts were...
Abstract An effective strategy to restore p53 activity in cancer cells containing wild type is inhibit the Mdm2-p53 protein-protein interaction (PPI). NVP-HDM201 a novel PPI inhibitor currently under evaluation Phase I clinical trial. It binds binding-site of Mdm2 protein, disrupting two proteins and leading activation pathway. belongs chemical series with distinct biophysical biochemical profile. Affinity constant for picomolar range, selectivity ratio greater than 10000-fold vs. Mdm4....
Abstract An effective strategy to restore p53 activity in cancer cells containing wild type is inhibit the Mdm2-p53 protein-protein interaction (PPI). NVP-CGM097 a novel PPI inhibitor under evaluation Phase I clinical trial. It binds binding-site of Mdm2 protein, disrupting between both proteins, leading an activation pathway. The main biophysical and biochemical inhibitory characteristics are presented here. These include affinity constant for nanomolar range selectivity 3 orders magnitude...
Abstract Activation of p53 by blocking the p53-Mdm2 interaction using non-peptidic small-molecule inhibitors has been pursued for many years as a promising cancer therapeutic strategy. We disclose identity NVP-HDM201, novel, highly optimized and selective inhibitor interaction. NVP-HDM201 binds to human Mdm2 protein with sub-nanomolar Ki value, activates induces robust p53-dependent cell cycle arrest apoptosis in wild-type tumor cells. The activity selectivity have tested confirmed across...
Abstract Stabilization of p53 protein by preventing its interaction with the negative regulator Mdm2 leads to selective induction pathway, thus offering a promising cancer therapeutic strategy in wild-type tumors. In present study, we show identification NVP-HDM201, novel, highly optimized, and inhibitor p53-Mdm2 interaction. NVP-HDM201 activates human cells induces robust p53-dependent cell cycle arrest apoptosis, selectively tumor cells. Its activity selectivity has been tested confirmed...