A5085494254- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
- Cancer-related gene regulation
- Cancer, Hypoxia, and Metabolism
- RNA modifications and cancer
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Chemical Synthesis and Analysis
- Protein Degradation and Inhibitors
- Prostate Cancer Treatment and Research
- Metabolomics and Mass Spectrometry Studies
- Mass Spectrometry Techniques and Applications
- Biochemical and Molecular Research
- Eicosanoids and Hypertension Pharmacology
- Polyamine Metabolism and Applications
- Metal-Catalyzed Oxygenation Mechanisms
- Tuberculosis Research and Epidemiology
- Invertebrate Immune Response Mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Mitochondrial Function and Pathology
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- Amino Acid Enzymes and Metabolism
- Pneumocystis jirovecii pneumonia detection and treatment
- Click Chemistry and Applications
Newcastle University
2020-2025
University of Oxford
2016-2025
Jumonji University
2025
Centre for Human Genetics
2013-2024
Oxford Research Group
2013-2020
Oxfam
2014-2018
Science Oxford
2014-2018
Mansfield University
2014
Wellcome Trust
2014
Center for Human Genetics
2014
Four compounds in clinical trials for anaemia treatment are potent inhibitors of the hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs), but differ potency and how they interact with HIF at PHD active site.
Abstract While the oxygen-dependent reversal of lysine N ɛ -methylation is well established, existence bona fide ω -methylarginine demethylases (RDMs) controversial. Lysine demethylation, as catalysed by two families (the flavin-dependent KDM1 enzymes and 2-oxoglutarate- JmjC KDMs, respectively), proceeds via oxidation -methyl group, resulting in release formaldehyde. Here we report detailed biochemical studies clearly demonstrating that, purified form, a subset KDMs can also act RDMs, both...
Background Small molecule modulators of epigenetic processes are currently sought as basic probes for biochemical mechanisms, and starting points development therapeutic agents. Nε-Methylation lysine residues on histone tails is one a number post-translational modifications that together enable transcriptional regulation. Histone demethylases antagonize the action methyltransferases in site- methylation state-specific manner. Nε-Methyllysine use 2-oxoglutarate co-factor associated with...
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...
Abstract The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and current cancer targets; however, very few highly selective inhibitors for these available. Here we report cyclic peptide of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures biochemical analyses one (CP2) KDM4A reveals that CP2 binds differently to, but competes with, substrates in active site. Substitution site binding arginine N...
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...
Methylation of lysine residues on histone tail is a dynamic epigenetic modification that plays key role in chromatin structure and gene regulation. Members the KDM5 (also known as JARID1) sub-family are 2-oxoglutarate (2-OG) Fe
In prostate cancer, two different types of histone lysine demethylases (KDM), LSD1/KDM1 and JMJD2/KDM4, are coexpressed colocalize with the androgen receptor. We designed synthesized hybrid LSD1/JmjC or "pan-KDM" inhibitors 1–6 by coupling skeleton tranylcypromine 7, a known LSD1 inhibitor, 4-carboxy-4′-carbomethoxy-2,2′-bipyridine 8 5-carboxy-8-hydroxyquinoline 9, 2-oxoglutarate competitive templates developed for JmjC inhibition. Hybrid compounds able to simultaneously target both KDM...
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...
We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind Fe(II) in active site. Substitution from C4 pyrazole moiety allows access peptide substrate binding site; incorporation conformationally constrained 4-phenylpiperidine linker gives such as 54j...
Abstract γ-Amino acids can play important roles in the biological activities of natural products; however, ribosomal incorporation γ-amino into peptides is challenging. Here we report how a selection campaign employing non-canonical peptide library containing cyclic γ 2,4 -amino resulted discovery very potent inhibitors SARS-CoV-2 main protease (M pro ). Two kinds acids, cis -3-aminocyclobutane carboxylic acid (γ 1 ) and (1 R ,3 S )-3-aminocyclopentane 2 ), were ribosomally introduced...
Abstract Due to their constrained conformations, cyclic β2,3-amino acids (cβAA) are key building blocks that can fold peptides into compact and rigid structures, improving peptidase resistance binding affinity target proteins, due conformations. Although the translation efficiency of cβAAs is generally low, our engineered tRNA, referred as tRNAPro1E2, enabled efficient incorporation peptide libraries using flexible in vitro (FIT) system. Here we report on design application a macrocyclic...
Histone Nε-methyl lysine demethylases KDM2/7 have been identified as potential targets for cancer therapies. On the basis of crystal structure KDM7B, we designed and prepared a series hydroxamate analogues bearing an alkyl chain. Enzyme assays revealed that compound 9 potently inhibits KDM2A, KDM7A, with IC50s 6.8, 0.2, 1.2 μM, respectively. While inhibitors KDM4s did not show any effect on cells tested, KDM2/7-subfamily inhibitor exerted antiproliferative activity, indicating anticancer agents.
The JmjC histone lysine demethylases (KDMs) are epigenetic regulators involved in the removal of methyl groups from post-translationally modified lysyl residues within tails, modulating gene transcription. These enzymes require molecular oxygen for catalytic activity and, as 2-oxoglutarate (2OG)-dependent oxygenases, related to cellular sensing HIF hydroxylases PHD2 and FIH. Recent studies have indicated that some KDMs, including pseudogene-encoded KDM4E, may be sensitive changing...
The JmjC-domain-containing 2-oxoglutarate-dependent oxygenases catalyze protein hydroxylation and Nϵ-methyllysine demethylation via hydroxylation. A subgroup of this family, the JmjC lysine demethylases (JmjC KDMs) are involved in histone modifications at multiple sites. There conflicting reports as to substrate selectivity some with respect KDM activities. In study, a panel modified H3 peptides was tested for against 15 human proteins. results largely confirmed known substrates. However,...
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...