A5056648248- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Histone Deacetylase Inhibitors Research
- Multiple Myeloma Research and Treatments
- Cytokine Signaling Pathways and Interactions
- interferon and immune responses
- Genomics and Chromatin Dynamics
- Peptidase Inhibition and Analysis
- Epigenetics and DNA Methylation
- Cardiac electrophysiology and arrhythmias
- Cancer, Hypoxia, and Metabolism
- Viral Infectious Diseases and Gene Expression in Insects
- Erythrocyte Function and Pathophysiology
- Trace Elements in Health
- Advanced biosensing and bioanalysis techniques
- Photoreceptor and optogenetics research
- RNA regulation and disease
- Chromatin Remodeling and Cancer
- Cardiac Fibrosis and Remodeling
- Blood properties and coagulation
- Cardiac Structural Anomalies and Repair
- Natural product bioactivities and synthesis
- Spectroscopy and Quantum Chemical Studies
- Advanced NMR Techniques and Applications
- Protein Structure and Dynamics
Goethe University Frankfurt
2016-2024
Structural Genomics Consortium
2019
University of Toronto
2019
Osaka University
2017
University of Bremen
2015
Creighton University
2008
Bromodomains (BRDs) are conserved protein interaction modules which recognize (read) acetyl-lysine modifications, however their role(s) in regulating cellular states and potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set 25 chemical probes, selective small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate selectivity this probe-set using BROMOscan demonstrate utility identifying roles...
YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation these modified lysine-binding has been linked to the onset and progression cancers. We herein report discovery characterisation first small-molecule chemical probe, SGC-iMLLT, for YD MLLT1 (ENL/YEATS1) MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent selective inhibitor MLLT1/3-histone interactions. Excellent selectivity over other human (YEATS2/4) bromodomains was observed....
Concomitant inhibition of anaplastic lymphoma kinase (ALK) and bromodomain-4 (BRD4) is a potential therapeutic strategy for targeting two key oncogenic drivers that co-segregate in significant fraction high-risk neuroblastoma patients, mutation ALK amplification MYCN. Starting from known dual polo-like (PLK)-1–BRD4 inhibitor BI-2536, we employed structure-based design to redesign this series toward compounds with ALK–BRD4 profile. These efforts led compound...
Histone acetyltransferases of the MYST family are recruited to chromatin by BRPF scaffolding proteins. We explored functional consequences and therapeutic potential inhibitors targeting acetyl-lysine dependent protein interaction domains (bromodomains) present in BRPF1-3 bone maintenance. report three potent selective inhibitors: one (PFI-4) with high selectivity for BRPF1B isoform two pan-BRPF bromodomain (OF-1, NI-57). The developed displaced bromodomains from did not inhibit cell growth...
Proteorhodopsins are widely distributed photoreceptors from marine bacteria. Their discovery revealed a high degree of evolutionary adaptation to ambient light, resulting in blue- and green-absorbing variants that correlate with conserved glutamine/leucine at position 105. On the basis an integrated approach combining sensitivity-enhanced solid-state nuclear magnetic resonance (ssNMR) spectroscopy linear-scaling quantum mechanics/molecular mechanics (QM/MM) methods, this single residue is...
Bromodomains (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, a selective ligand the fifth BRD polybromo protein-1 (PB1(5)) related to switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes is presented. A compound collection was evaluated by consensus virtual screening and hit identified. The biophysical study protein–ligand interactions performed using X-ray...
Lysine acetylation is an epigenetic mark that principally recognized by bromodomains, and recently structurally diverse YEATS domains also emerged as readers of lysine acetyl/acylations. Here we present a crystallography-based strategy the discovery fragments binding to ENL domain, potential drug target. Crystal structures combined with synthetic efforts led identification submicromolar binder, providing first starting points for development chemical probes this reader domain family.
Accessibility of the human genome is modulated by ATP-driven SWI/SNF chromatin remodeling multiprotein complexes BAF (BRG1/BRM-associated factor) and PBAF (polybromo-associated factor), which involves reading acetylated histone tails bromodomain-containing proteins SMARCA2 (BRM), SMARCA4 (BRG1), polybromo-1. Dysregulation leads to aberrant cell proliferation differentiation. Here, we have characterized a set potent cell-active bromodomain inhibitors with pan-selectivity for canonical family...
YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as mimetic moiety for MLLT1. Crystal structures revealed interaction mechanisms this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within protein. Thus, scaffold offers alternative...
The chemopreventive and anticancer effects of resveratrol (RSV) are widely reported in the literature. Specifically, mechanisms involving epigenetic regulation promising targets to regulate tumor development. Bromodomains act as readers by recognizing lysine acetylation on histone tails boosting gene expression order tissue-specific transcription. In this work, we showed that RSV is a pan-BET inhibitor. Using Differential Scanning Fluorimetry (DSF), at 100 µM increased melting temperature...
Summary Bromodomains (BRDs) are evolutionary conserved epigenetic protein interaction modules which recognize (“read”) acetyl-lysine, however their role(s) in regulating cellular states and potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set 25 chemical probes, selective tool small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate selectivity this probe-set using BROMOscan ® demonstrate...
Abstract Elevated homocysteine (Hcys) increases the risk of neurocristopathies. Previous studies show Hcys inhibits neural crest (NC) cell migration in vivo. However, mechanisms responsible for this effect are unknown. Here, we evaluated on NC attachment vitro and determined if any effects were due to altered Ca 2+ signaling. We found enhanced a dose substrate‐dependent manner. Ionomycin mimicked while BAPTA‐AM 2‐APB blocked attachment. In contrast, inhibitors plasma membrane channels had no...
<p>YEATS domain (YD) containing proteins are an emerging</p> <p>class of epigenetic targets in drug discovery. Dysregulation these modified lysine binding has been linked to the onset and progression cancers. We herein report discovery characterisation first small molecule chemical probe, SGC-iMLLT, for YD MLLT1 (ENL/YEATS1) MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent selective inhibitor MLLT1/3 -histone interactions. Excellent selectivity over other human (YEATS2/4)...
ABSTRACT Lysine acetylation is an epigenetic mark that principally recognized by bromodomains and recently structurally diverse YEATS domains also emerged as readers of lysine acetyl/acylations. Here we present a crystallography-based strategy the discovery fragments binding to ENL domain, potential drug target. Crystal structures combined with synthetic efforts led identification sub-micromolar binder, providing first starting points for development chemical probes this reader domain family.
Abstract YEATS‐Domänen(YD)‐enthaltende Proteine sind eine neue Klasse epigenetischer Zielstrukturen für die Wirkstoffentwicklung. Die YD‐enthaltenden MLLT1 (ENL/YEATS1) und MLLT3 (AF9/MLLT3) oft in Krebs dereguliert wurden daher als potentielle Therapieansätze diskutiert. Wir berichten hier Entwicklung Charakterisierung des ersten niedermolekularen Inhibitors der YD MLLT3, SGC‐iMLLT . Er ist ein potenter selektiver Inhibitor MLLT1/3‐Histon‐Interaktion zeichnet sich durch exzellente...
ABSTRACT YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as mimetic moiety for MLLT1. Crystal structures revealed interaction mechanisms this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within protein. Thus, scaffold offers...
YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation these modified lysine binding has been linked to the onset and progression cancers. We herein report discovery characterisation first small molecule chemical probe, SGC-iMLLT, for YD MLLT1 (ENL/YEATS1) MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent selective inhibitor MLLT1/3 -histone interactions. Excellent selectivity over other human (YEATS2/4) bromodomains was observed....