A5037087454- Cancer, Hypoxia, and Metabolism
- Metabolomics and Mass Spectrometry Studies
- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
- Metal-Catalyzed Oxygenation Mechanisms
- Mitochondrial Function and Pathology
- High Altitude and Hypoxia
- Fuel Cells and Related Materials
- Peroxisome Proliferator-Activated Receptors
- Cancer-related Molecular Pathways
- Cancer-related gene regulation
- Zebrafish Biomedical Research Applications
- Ubiquitin and proteasome pathways
- Single-cell and spatial transcriptomics
- Mass Spectrometry Techniques and Applications
- interferon and immune responses
- Genomics, phytochemicals, and oxidative stress
- Adipose Tissue and Metabolism
- Catalytic C–H Functionalization Methods
- Synthetic Organic Chemistry Methods
- RNA modifications and cancer
- Kruppel-like factors research
- Eicosanoids and Hypertension Pharmacology
- Quinazolinone synthesis and applications
- Protein Degradation and Inhibitors
University of Malaya
2020-2023
University of Oxford
2012-2020
MRC Weatherall Institute of Molecular Medicine
2010-2016
Science Oxford
2015
Nuffield Health
2015
2-Oxoglutarate and iron dependent oxygenases are therapeutic targets for human diseases. Using a representative 2OG oxygenase panel, we compare the inhibitory activities of 5-carboxy-8-hydroxyquinoline (IOX1) 4-carboxy-8-hydroxyquinoline (4C8HQ) with that two other commonly used inhibitors, N-oxalylglycine (NOG) 2,4-pyridinedicarboxylic acid (2,4-PDCA). The results reveal IOX1 has broad spectrum activity, as demonstrated by inhibition transcription factor hydroxylases, representatives all...
The JmjC oxygenases catalyze the N-demethylation of N(ε)-methyl lysine residues in histones and are current therapeutic targets. A set human 2-oxoglutarate analogues were screened using a unified assay platform for demethylases related oxygenases. Results led to finding that daminozide (N-(dimethylamino)succinamic acid, 160 Da), plant growth regulator, selectively inhibits KDM2/7 subfamily. Kinetic crystallographic studies reveal chelates active site metal via its hydrazide carbonyl...
The hypoxia inducible factor (HIF) system is central to the signaling of low oxygen (hypoxia) in animals. levels HIF-α isoforms are regulated an oxygen-dependent manner by activity HIF prolyl-hydroxylases (PHD or EGLN enzymes), which Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases. Here, we describe biochemical, crystallographic, cellular profiling, animal studies on PHD inhibitors including selectivity using a representative set human 2OG We identify suitable probe compounds for use...
Dynamic duo: The reversible reaction of boronic acids with alcohols to form boronate esters, coupled protein mass spectrometry analyses, was used discover potent oxygenase inhibitors. This dynamic combinatorial technique could potentially be applied the identification other
The 2-oxoglutarate (2OG)-dependent Jumonji C domain (JmjC) family is the largest of histone lysine demethylases. There interest in developing small-molecule probes that modulate JmjC activity to investigate their biological roles. 5-Carboxy-8-hydroxyquinoline (IOX1) most potent broad-spectrum inhibitor 2OG oxygenases, including demethylases, reported date; however, it suffers from low cell permeability. Here, we describe structure-activity relationship studies leading discovery an n-octyl...
Transcription factor (TF) networks determine cell-type identity by establishing and maintaining lineage-specific expression profiles, yet reconstruction of mammalian regulatory network models has been hampered a lack comprehensive functional validation interactions. Here, we report ChIP-Seq, transgenic reporter gene experimental data that have allowed us to construct an experimentally validated model for haematopoietic stem/progenitor cells (HSPCs). Model simulation coupled with subsequent...
Select an isoform: Linking of cosubstrate and substrate binding sites enables highly selective inhibiton isoforms human histone lysine demethylases. The results should provide a basis for the development potent JmjC inhibitors, possibly suitable clinical use. Detailed facts importance to specialist readers are published as "Supporting Information". Such documents peer-reviewed, but not copy-edited or typeset. They made available submitted by authors. Please note: publisher is responsible...
As part of the cellular adaptation to limiting oxygen availability in animals, expression a large set genes is activated by upregulation hypoxia-inducible transcription factors (HIFs). Therapeutic activation natural human hypoxic response can be achieved inhibition hypoxia sensors for HIF system, i.e. prolyl-hydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with 2-oxoglutarate co-substrate. One...
Abstract The cellular transcriptional response to hypoxia is regulated by hypoxia‐inducible factor (HIF). In lung cancer, elevated levels of HIF expression are linked poor prognosis and aggressive disease. Inhibitors the prolyl hydroxylases (PHDs) induce a hypoxic upregulating currently used treat anemia associated with chronic kidney disease stimulating erythropoietin production. However, it unclear whether high induced these PHD inhibitors (PHIs) could promote cancer progression. Here,...
2-Oxoglutarate-dependent nucleic acid demethylases are of biological interest because their roles in repair and modification. Although some these enzymes linked to physiology, regulatory unclear. Hence, there is a desire develop selective inhibitors for them; we report studies on AlkB, which reveal it as being amenable inhibition by small molecules. Dynamic combinatorial chemistry mass spectrometric analyses (DCMS) led the identification lead compounds, one was analyzed crystallography....
A Betti reaction was used for efficient generation of 2OG oxygenase inhibitors, including KDM4 demethylases.
Dynamisches Duo: Die reversible Reaktion von Boronsäuren mit Alkoholen zu Boronatestern wurde genutzt, um, in Verbindung massenspektrometrischen Proteinanalysen, potente Oxygenase-Inhibitoren finden. Diese dynamische kombinatorische Massenspektrometrietechnik könnte auch auf die Identifizierung anderer Protein-Inhibitoren angewendet werden.
Inhibition of the hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD or EGLN enzymes) is interest for treatment anemia and ischemia-related diseases. Most PHD inhibitors work by binding to single ferrous ion competing with 2-oxoglutarate (2OG) co-substrate at active site. Non-specific iron chelators also inhibit PHDs, both in vitro cells. We report identification dual action inhibitors, which bind site induce a second Following analysis small-molecule complexes application...
The hypoxia-inducible factors (HIFs) are key transcription in determining cellular responses involving alterations protein levels response to limited oxygen availability animal cells. 2-Oxoglutarate-dependent oxygenases play roles regulating of HIF and its transcriptional activity. We describe MS-based proteomics studies which we compared the results subjecting human breast cancer MCF-7 cells hypoxia or treating them with a cell-penetrating derivative (dimethyl N-oxalylglycine; DMOG) stable...
Wähle eine Isoform: Durch Verbrücken von Cosubstrat- und Substratbindungsstellen gelingt hoch selektive Inhibierung Isoformen humaner Histonlysin-Demethylasen. Die Ergebnisse bieten Grundlage für die Entwicklung potenten selektiven JmjC-Inhibitoren mit möglicher Eignung den klinischen Einsatz.