A5081590980- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- Protein Degradation and Inhibitors
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA modifications and cancer
- Acute Myeloid Leukemia Research
- Ubiquitin and proteasome pathways
- Lymphoma Diagnosis and Treatment
- Glycosylation and Glycoproteins Research
- Chromatin Remodeling and Cancer
- Acute Lymphoblastic Leukemia research
- Microbial Natural Products and Biosynthesis
- Immune Response and Inflammation
- Cancer therapeutics and mechanisms
- Immunodeficiency and Autoimmune Disorders
- Alzheimer's disease research and treatments
- Galectins and Cancer Biology
- Histone Deacetylase Inhibitors Research
- RNA Interference and Gene Delivery
- Cancer Mechanisms and Therapy
- Chronic Lymphocytic Leukemia Research
- Peptidase Inhibition and Analysis
- Nuclear Receptors and Signaling
- CRISPR and Genetic Engineering
- Protein Kinase Regulation and GTPase Signaling
University of Bonn
2018-2024
University Hospital Bonn
2018-2024
Woomera Therapeutics
2021-2024
Akebia Therapeutics (United States)
2019-2020
Epizyme (United States)
2012-2018
University of Freiburg
2015
Eisai (Japan)
2014
Humboldt-Universität zu Berlin
2008-2011
Charité - Universitätsmedizin Berlin
2008
Inactivation of the switch/sucrose nonfermentable complex component SMARCB1 is extremely prevalent in pediatric malignant rhabdoid tumors (MRTs) or atypical teratoid tumors. This alteration hypothesized to confer oncogenic dependency on EZH2 these cancers. We report discovery a potent, selective, and orally bioavailable small-molecule inhibitor enzymatic activity,...
Mutations within the catalytic domain of histone methyltransferase EZH2 have been identified in subsets patients with non-Hodgkin lymphoma (NHL). These genetic alterations are hypothesized to confer an oncogenic dependency on enzymatic activity these cancers. We previously reported discovery EPZ005678 and EPZ-6438, potent selective S-adenosyl-methionine-competitive small molecule inhibitors EZH2. Although both compounds similar respect their mechanism action selectivity, EPZ-6438 possesses...
Abstract Toll-like receptor–driven and interleukin-1 (IL-1) inflammation mediated by IL-1 receptor–associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) atopic dermatitis (AD). KT-474 (SAR444656), an IRAK4 degrader, was studied a randomized, double-blind, placebo-controlled phase 1 trial where primary objective safety tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics clinical activity patients with moderate to severe HS...
Inhibitors of the protein methyltransferase Enhancer Zeste Homolog 2 (EZH2) may have significant therapeutic potential for treatment B cell lymphomas and other cancer indications. The ability scientific community to explore fully spectrum EZH2-associated pathobiology has been hampered by lack in vivo-active tool compounds this enzyme. Here we report discovery characterization EPZ011989, a potent, selective, orally bioavailable inhibitor EZH2 with useful pharmacokinetic properties. EPZ011989...
EPZ-5676 [(2<i>R</i>,3<i>R</i>,4<i>S</i>,5<i>R</i>)-2-(6-amino-9<i>H</i>-purin-9-yl)-5-((((1<i>r</i>,3<i>S</i>)-3-(2-(5-(<i>tert</i>-butyl)-1<i>H</i>-benzo[<i>d</i>]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol], a small-molecule inhibitor of the protein methyltransferase DOT1L, is currently under clinical investigation for acute leukemias bearing <i>MLL</i>-rearrangements (<i>MLL</i>-r). In this study, we evaluated in combination with standard care (SOC)...
Abstract Background Tazemetostat (EPZ‐6438) is a selective inhibitor of the histone methyltransferase EZH2 and currently in clinical development for non‐Hodgkin lymphoma genetically defined tumors. Procedures was tested against Pediatric Preclinical Testing Program (PPTP) solid tumor xenografts using dose 400 mg/kg administered twice daily by oral gavage 28 days. H3K27me3:H3 ratios were determined control treated Results induced significant differences event‐free survival (EFS) distribution...
The microglial triggering receptor expressed on myeloid cells 2 (TREM2) signals via the activatory membrane adaptor molecule TYROBP. Genetic variants or mutations of TREM2 TYROBP have been linked to inflammatory neurodegenerative diseases associated with aging. typical aging process goes along changes and mild neuronal loss, but exact contribution is still unclear. Aged knock-out mice showed decreased age-related loss in substantia nigra hippocampus. Transcriptomic analysis brains 24 months...
Developing therapies for the activated B-cell like (ABC) subtype of diffuse large lymphomas (DLBCL) remains an area unmet medical need. A subset ABC DLBCL tumors is driven by activating mutations in myeloid differentiation primary response protein 88 (MYD88), which lead to constitutive activation interleukin-1 receptor associated kinase 4 (IRAK4) and cellular proliferation. IRAK4 signaling its catalytic scaffolding functions, necessitating complete removal this escape mechanisms therapeutic...
Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential mediator of the IL-1R and TLR signaling pathways, both which have been implicated in multiple autoimmune conditions. Hence, blocking activity IRAK4 represents attractive approach for treatment diseases. The this serine/threonine dependent on its scaffolding activities; thus, degradation a potentially superior to inhibition. Herein, we detail exploration structure-activity relationships that ultimately led identification...
SMYD3 has been implicated in a range of cancers; however, until now no potent selective small molecule inhibitors have available for target validation studies. A novel oxindole series was identified through screening the Epizyme proprietary histone methyltransferase-biased library. Potency optimization afforded two tool compounds, sulfonamide EPZ031686 and sulfamide EPZ030456, with cellular potency at level sufficient to probe vitro biology inhibition. shows good bioavailability following...
Patients with non-Hodgkin lymphoma (NHL) are treated today a cocktail of drugs referred to as CHOP (Cyclophosphamide, Hydroxyldaunorubicin, Oncovin, and Prednisone). Subsets patients NHL germinal center origin bear oncogenic mutations in the EZH2 histone methyltransferase. Clinical testing inhibitor EPZ-6438 has recently begun patients. We report here that combining preclinical cell culture mouse models results dramatic synergy for killing mutant cells. Surprisingly, we observe much this is...
ABSTRACT (2 R ,3 ,4 S ,5 )‐2‐(6‐Amino‐9 H ‐purin‐9‐yl)‐5‐((((1 r )‐3‐(2‐(5‐( tert ‐butyl)‐1 ‐benzo[ d ]imidazol‐2‐yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran‐3,4‐diol (EPZ‐5676) is a novel DOT1L histone methyltransferase inhibitor currently in clinical development for the treatment of MLL‐rearranged leukemias. This report describes preclinical pharmacokinetics and metabolism EPZ‐5676, an aminonucleoside analog with exquisite target potency selectivity that has shown robust...
Aging is regarded as a major risk factor for neurodegenerative diseases. Thus, better understanding of the similarities between aging process and diseases at cellular molecular level may reveal this detrimental relationship. In present study, we mined publicly available gene expression datasets from healthy individuals patients affected by (Alzheimer's disease, Parkinson's disease Huntington's disease) across broad age spectrum compared those with mouse cell-type specific profiles. We...
A key challenge in the development of precision medicine is defining phenotypic consequences pharmacological modulation specific target macromolecules. To address this issue, a variety genetic, molecular and chemical tools can be used. All these approaches produce misleading results if specificity not well understood proper controls are performed. In paper we illustrate general themes by providing detailed studies small molecule inhibitors enzymatic activity two members SMYD branch protein...
Sialic acid-binding Ig-like lectin (Siglec) receptors are linked to neurodegenerative processes, but the role of sialic acids in physiological aging is still not fully understood. We investigated impact reduced sialylation brain mice heterozygous for enzyme glucosamine-2-epimerase/N-acetylmannosamine kinase (GNE+/−) that essential acid biosynthesis. demonstrate GNE+/− have hyposialylation different regions, less synapses hippocampus and microglial arborization already at 6 months followed by...
Abstract Parkinson's disease is one of the most common neurodegenerative diseases in elderly population, with a pathophysiology linked to neuroinflammation, complement activation, and oxidative damage. Soluble polysialic acid an average degree polymerization 20 (polySia avDP20) prevents inflammation burst human macrophages via sialic acid‐binding immunoglobulin like lectin‐11 (SIGLEC11) receptor interferes alternative activation. Here, we confirmed anti‐inflammatory capacity polySia avDP20...
TPS3171 Background: The signal transducer and activator of transcription 3 (STAT3) protein is activated by cytokines growth factors resulting in tumor promotion hindering antitumor immunity. Approximately 70% human cancers including both hematological malignancies solid tumors exhibit increased levels phosphorylated STAT3 (pSTAT3). There evidence constitutive activation through genetic mutations or aberrant cellular signaling pathways such as large granular lymphocytic leukemia (LGL-L),...
Abstract Recently we described an unusual way of activating a cryptic gene cluster when explored the origin bald phenotype Streptomyces calvus . Complementation S. with correct copy bldA restored sporulation and additionally promoted production new natural products. In this study report on expression in several strains that have been as “poorly sporulating” strains. seven out 15 cases, HPLC profiling revealed compounds, two cases overproduction known compounds. Two compounds were isolated...
Sic1, cyclin-dependent kinase inhibitor of budding yeast, is synthesized in anaphase and largely degraded at the S-phase onset to regulate timing DNA synthesis. Sic1 interacts with phase-specific B-type cyclin (Clb)-kinase (Cdk1) complexes, central regulators cell cycle control. Its appearance timed mediate reduction activities appropriate stages. Clbs are unstable proteins extremely short half-lives. Interactions have been detected both vitro vivo by high-throughput genome-wide screenings....
Brain aging is a chronic process linked to inflammation, microglial activation, and oxidative damage, which can ultimately lead neuronal loss. Sialic acid-binding immunoglobulin-like lectin-11 (SIGLEC-11) human lineage-specific cell surface receptor that recognizes α -2-8-linked oligo−/polysialylated glycomolecules with inhibitory effects on the inflammatory pathways. Recently, SIGLEC11 gene locus was prioritized as top tier potential causality Alzheimer’s disease, although its role in...