A5064686912- Radioactive element chemistry and processing
- Protein Degradation and Inhibitors
- Mass Spectrometry Techniques and Applications
- Medical Imaging Techniques and Applications
- Machine Learning in Materials Science
- Computational Drug Discovery Methods
- Click Chemistry and Applications
- Histone Deacetylase Inhibitors Research
- Nuclear Materials and Properties
- Ubiquitin and proteasome pathways
- Catalysis and Oxidation Reactions
- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- Peptidase Inhibition and Analysis
- Chemical Thermodynamics and Molecular Structure
- Multiple Myeloma Research and Treatments
- Biochemical and Molecular Research
- Cancer Mechanisms and Therapy
- Metabolism and Genetic Disorders
- Chronic Myeloid Leukemia Treatments
- Chronic Lymphocytic Leukemia Research
- Cytokine Signaling Pathways and Interactions
- Chemical Synthesis and Analysis
- RNA Research and Splicing
- Lung Cancer Treatments and Mutations
University of Oxford
2016-2025
Discovery Centre
2022
Genomics (United Kingdom)
2015-2021
Genomics England
2016-2020
Discovery Institute
2020
Target (United States)
2020
Science Oxford
2020
Ludwig-Maximilians-Universität München
2007-2019
CeMM Research Center for Molecular Medicine
2011-2017
Austrian Academy of Sciences
2011-2017
Type 1 diabetes is characterized by the destruction of pancreatic β cells, and generating new insulin-producing cells from other cell types a major aim regenerative medicine. One promising approach transdifferentiation developmentally related types, including glucagon-producing α cells. In genetic model, loss master regulatory transcription factor Arx sufficient to induce conversion functional β-like Here, we identify artemisinins as small molecules that functionally repress causing its...
Covalent probes can display unmatched potency, selectivity, and duration of action; however, their discovery is challenging. In principle, fragments that irreversibly bind target overcome the low affinity limits reversible fragment screening, but such electrophilic were considered nonselective rarely screened. We hypothesized mild electrophiles might selectivity challenge constructed a library 993 mildly fragments. characterized this by new high-throughput thiol-reactivity assay screened...
For kinase inhibitors, intracellular target selectivity is fundamental to pharmacological mechanism. Although a number of acellular techniques have been developed measure binding or enzymatic inhibition, such approaches can fail accurately predict engagement in cells. Here we report the application an energy transfer technique that enabled first broad-spectrum, equilibrium-based approach quantitatively profile occupancy and compound affinity live Using this method, performed profiling for...
There is a growing recognition of the importance protein kinases in control alternative splicing. To define underlying regulatory mechanisms, highly selective inhibitors are needed. Here, we report discovery and characterization dichloroindolyl enaminonitrile KH-CB19, potent specific inhibitor CDC2-like kinase isoforms 1 4 (CLK1/CLK4). Cocrystal structures KH-CB19 with CLK1 CLK3 revealed non-ATP mimetic binding mode, conformational changes helix αC phosphate loop halogen bonding to hinge...
Abstract Necroptosis is a form of regulated necrotic cell death mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3. Necroptotic contributes to the pathophysiology several disorders involving tissue damage, including myocardial infarction, stroke ischemia-reperfusion injury. However, no inhibitors necroptosis are currently in clinical use. Here we performed phenotypic screen for small-molecule tumor necrosis factor-alpha (TNF -α )-induced Fas-associated...
The RAPTA pharmacophore was linked to beads identify its biomolecular targets in cancer cells.
Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present collection chemical probes and associated reagents data to elucidate the function human murine PMTs in cellular studies. Our provides inhibitors antagonists that together modulate most key methylation marks on histones H3 H4, providing an important resource for modulating epigenomes. We describe comprehensive comparative characterization probe respect their...
Abstract Concerted multidisciplinary efforts have led to the development of Cyclin-Dependent Kinase inhibitors (CDKi’s) as small molecule drugs and chemical probes intracellular CDK function. However, conflicting data has been reported on inhibitory potency CDKi’s a systematic characterization affinity selectivity against CDKs is lacking. We developed panel cell-permeable energy transfer quantify target occupancy for all 21 human in live cells, present comprehensive evaluation isozyme...
The provirus integration site for Moloney murine leukemia virus 1 (Pim-1) kinase is overexpressed in various tumors and has been linked to poor prognosis. Its role as proto-oncogene based on several Pim-1 target proteins involved pivotal cellular processes. Here, we explore the functional relevance of colon carcinoma.RNAi-based knockdown approaches, well a specific small molecule inhibitor, were used inhibit carcinoma cells. effects analyzed regarding proliferation, apoptosis, sensitization...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTotal synthesis of talatisamine, a delphinine type alkaloidK. Wiesner, T. Y. R. Tsai, K. Huber, S. E. Bolton, and VlahovCite this: J. Am. Chem. Soc. 1974, 96, 15, 4990–4992Publication Date (Print):July 1, 1974Publication History Published online1 May 2002Published inissue 1 July 1974https://pubs.acs.org/doi/10.1021/ja00822a048https://doi.org/10.1021/ja00822a048research-articleACS PublicationsRequest reuse permissionsArticle...
ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading discovery BAY-850, potent isoform selective inhibitor that specifically induces bromodomain dimerization prevents interactions with acetylated histones in vitro, as well chromatin cells. These features qualify BAY-850 chemical probe explore biology.
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....
Abstract The p300/CBP‐associated factor (PCAF) and related GCN5 bromodomain‐containing lysine acetyl transferases are members of subfamily I the bromodomain phylogenetic tree. Iterative cycles rational inhibitor design biophysical characterization led to discovery triazolopthalazine‐based L‐45 (dubbed L‐Moses ) as first potent, selective, cell‐active PCAF (Brd) inhibitor. Synthesis from readily available (1R,2S)‐(−)‐norephedrine furnished in enantiopure form. was shown disrupt PCAF‐Brd...