A5021643069- Liver physiology and pathology
- Cancer, Hypoxia, and Metabolism
- Cancer Cells and Metastasis
- Ubiquitin and proteasome pathways
- Lung Cancer Treatments and Mutations
- Peptidase Inhibition and Analysis
- Pancreatic and Hepatic Oncology Research
- Multiple Myeloma Research and Treatments
- Pharmacogenetics and Drug Metabolism
- Cancer Mechanisms and Therapy
- Hepatocellular Carcinoma Treatment and Prognosis
- Pancreatic function and diabetes
- PI3K/AKT/mTOR signaling in cancer
- Cancer therapeutics and mechanisms
- Neuroscience and Neuropharmacology Research
- Heat shock proteins research
- TGF-β signaling in diseases
- Cancer Research and Treatments
- Protein Degradation and Inhibitors
- Chemical Synthesis and Analysis
- Chemical Reactions and Isotopes
- FOXO transcription factor regulation
- Cancer and biochemical research
- Caveolin-1 and cellular processes
- Drug Transport and Resistance Mechanisms
Merck (Germany)
2010-2023
Merck Serono (Italy)
2015
Goethe University Frankfurt
2006-2012
Abstract Purpose: The mesenchymal–epithelial transition factor (c-Met) receptor, also known as hepatocyte growth receptor (HGFR), controls morphogenesis, a process that is physiologically required for embryonic development and tissue repair. Aberrant c-Met activation associated with variety of human malignancies including cancers the lung, kidney, stomach, liver, brain. In this study, we investigated properties two novel compounds developed to selectively inhibit in antitumor therapeutic...
Proteasomes are broadly expressed key components of the ubiquitin-dependent protein degradation pathway containing catalytically active subunits (β1, β2, and β5). LMP7 (β5i) is a subunit immunoproteasome, an inducible isoform that predominantly in hematopoietic cells. Clinically effective pan-proteasome inhibitors for treatment multiple myeloma (MM) nonselectively target other constitutive proteasome immunoproteasome with comparable potency, which can limit therapeutic applicability these...
Abstract Large multifunctional peptidase 7 (LMP7/β5i/PSMB8) is a proteolytic subunit of the immunoproteasome, which predominantly expressed in normal and malignant hematolymphoid cells, including multiple myeloma, contributes to degradation ubiquitinated proteins. Described herein for first time preclinical profile M3258; an orally bioavailable, potent, reversible highly selective LMP7 inhibitor. M3258 demonstrated strong antitumor efficacy myeloma xenograft models, novel model human bone...
The RON tyrosine kinase receptor is under investigation as a novel target in pancreatic cancer. While mutations are uncommon, isoforms produced cancer cells via variety of mechanisms. In this study we sought to: 1) characterize isoform expression cancer, 2) investigate mechanisms that regulate expression, and 3) determine how various effect gene oncogenic phenotypes responses to directed therapies. We quantified transcripts human found levels 2500 fold normal pancreas with comprising nearly...
The elongated structures of polyamine inverse agonists such as 1,12-diaminododecane (N12N) and 5-(4-aminobutyl)-2-thiopheneoctanamine (N4T8N) lend themselves to a combinatorial chemistry approach explore potential pharmacophore at the NMDA receptor. Herein we describe more than 100 new analogues N4T8N obtained by breaking up long octanamine arm into dipeptide chain equivalent length. Solid-phase parallel synthesis based on cross-linked polystyrene Wang anchor allowed low-scale preparation...
Abstract Large multifunctional peptidase 7 (LMP7, β5i, PSMB8) is a chymotrypsin-like proteolytic subunit of the immunoproteasome, which degrades ubiquitinated proteins and generates peptides for presentation on MHC class I. In contrast to constitutive proteasome, broadly expressed, immunoproteasome specifically present in normal malignant hematopoietic cells can be induced non-hematopoietic by inflammatory stimuli such as IFNγ. Pan-proteasome inhibitors like Bortezomib, approved multiple...
Abstract Proteasomes are large multi-subunit proteolytic complexes which key components of the ubiquitin-dependent protein degradation pathway. The constitutive proteasome is an isoform expressed in most tissues, where it regulates homeostasis. In contrast, immunoproteasome predominantly hematopoietic cells and can be induced non-hematopoietic by inflammatory stimuli such as IFNγ. contains catalytically different subunits β1c, β2c β5c, possess caspase-like, trypsin-like chymotrypsin-like...
Abstract c-Met, the receptor for hepatocyte growth factor (HGF), is a well characterized tyrosine kinase, which crucial cell functions, such as survival, proliferation, motility and migration. Activating point mutations of c-Met have been identified in human malignancies, including renal carcinoma lung cancer constitutive activation HGF/c-Met pathway leads to tumor development progression animal models. In light these findings, has become key target oncology therapeutics. order develop...
Intracellular distribution of drug compounds is dependent on physicochemical characteristics and may have a significant bearing the extent target occupancy and, ultimately, efficacy. We assessed differences in profiles MET inhibitors capmatinib, crizotinib, savolitinib, tepotinib their effects cell viability phosphorylation under steady-state washout conditions (to mimic an open organic system) human lung cancer line. To examine underlying molecular mechanisms at receptor level, we...
<div>Abstract<p>Large multifunctional peptidase 7 (LMP7/β5i/PSMB8) is a proteolytic subunit of the immunoproteasome, which predominantly expressed in normal and malignant hematolymphoid cells, including multiple myeloma, contributes to degradation ubiquitinated proteins. Described herein for first time preclinical profile M3258; an orally bioavailable, potent, reversible highly selective LMP7 inhibitor. M3258 demonstrated strong antitumor efficacy myeloma xenograft models, novel...
<p>Supplemental Data and Methods</p>
<p>Supplemental Data and Methods</p>
<div>Abstract<p>Large multifunctional peptidase 7 (LMP7/β5i/PSMB8) is a proteolytic subunit of the immunoproteasome, which predominantly expressed in normal and malignant hematolymphoid cells, including multiple myeloma, contributes to degradation ubiquitinated proteins. Described herein for first time preclinical profile M3258; an orally bioavailable, potent, reversible highly selective LMP7 inhibitor. M3258 demonstrated strong antitumor efficacy myeloma xenograft models, novel...
Abstract The involvement of the mesenchymal endothelial transition factor (c-Met) in primary event oncogenic transformation and secondary ability to mediate metastatic spread has been convincingly demonstrated preclinical early clinical settings. benefits c-Met kinase inhibitors with various modes actions selectivity profiles are currently under investigation hoping that might emerge as valuable cancer therapeutics future. During an HTS run 3-(diethylamino)propyl...
<div>Abstract<p>The mesenchymal–epithelial transition factor (<i>MET</i>) proto-oncogene encodes the MET receptor tyrosine kinase. <i>MET</i> aberrations drive tumorigenesis in several cancer types through a variety of molecular mechanisms, including mutations, gene amplification, rearrangement, and overexpression. Therefore, is therapeutic target selective type Ib inhibitor, tepotinib, was designed to potently inhibit kinase activity. <i>In...
Abstract The role of the receptor tyrosin kinase c-Met in tumor progression, metastasis and aggressiveness has been convincingly demonstrated preclinical early clinical settings. Several compounds with different selectivity profiles inhibiting are currently under preclinical/clinical investigation might emerge as valuable cancer therapeutics future. During an HTS run N-(3-(3,6-Dihydro-5-(3,4-dimethoxyphenyl)-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl)-phenyl)-carbaminic...
Large multifunctional peptidase 7 (LMP7, β5i, PSMB8) is a chymotrypsin-like proteolytic subunit of the immunoproteasome, which degrades ubiquitinated proteins and generates peptides for presentation on MHC class I. In contrast to constitutive proteasome, broadly expressed, immunoproteasome specifically present in normal malignant hematopoietic cells can be induced non-hematopoietic by inflammatory stimuli such as IFNγ. Pan-proteasome inhibitors like Bortezomib, approved multiple myeloma...
Proteasomes are large multi-subunit proteolytic complexes which key components of the ubiquitin-dependent protein degradation pathway. The constitutive proteasome is an isoform expressed in most tissues, where it regulates homeostasis. In contrast, immunoproteasome predominantly hematopoietic cells and can be induced non-hematopoietic by inflammatory stimuli such as IFNγ. contains catalytically different subunits β1c, β2c β5c, possess caspase-like, trypsin-like chymotrypsin-like activity,...
Abstract The mesenchymal-epithelial transition factor (c-Met) receptor, also known as hepatocyte growth receptor (HGFR), controls morphogenesis, a process physiologically required for embryonic development and tissue repair. Aberrant c-Met activation is associated with human malignancies, including hepatocellular carcinomas (HCC). aim of this study was to evaluate the effect novel, highly selective inhibitor, MSC2156119J (EMD 1214063), in cancer models. MHCC97H HCC cell line co-expressing...
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