11 results on '"Christott, T"'
Search Results
2. Crystal structure of S100A4 labeled with NU000846b.
- Author
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Giroud, C., primary, Szommer, T., additional, Coxon, C., additional, Monteiro, O., additional, Christott, T., additional, Bennett, J., additional, Aitmakhanova, K., additional, Raux, B., additional, Newman, J., additional, Elkins, J., additional, Arruda Bezerra, G., additional, Krojer, T., additional, Koekemoer, L., additional, Von Delft, F., additional, Bountr, C., additional, Brennan, P., additional, and Fedorov, O., additional more...
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- 2022
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3. Differential occupational risks to healthcare workers from SARS-CoV-2 observed during a prospective observational study
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Eyre, DW, Lumley, SF, O'Donnell, D, Campbell, M, Sims, E, Lawson, E, Warren, F, James, T, Cox, S, Howarth, A, Doherty, G, Hatch, SB, Kavanagh, J, Chau, KK, Fowler, PW, Swann, J, Volk, D, Yang-Turner, F, Stoesser, N, Matthews, PC, Dudareva, M, Davies, T, Shaw, RH, Peto, L, Downs, LO, Vogt, A, Amini, A, Young, BC, Drennan, PG, Mentzer, AJ, Skelly, DT, Karpe, F, Neville, MJ, Andersson, M, Brent, AJ, Jones, N, Martins Ferreira, L, Christott, T, Marsden, BD, Hoosdally, S, Cornall, R, Crook, DW, Stuart, DI, Screaton, G, Group, Oxford University Hospitals Staff Testing, Watson, AJ, Taylor, A, Chetwynd, A, Grassam-Rowe, A, Mighiu, AS, Peck, LJ, Ebner, D, and Conlon, CP more...
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Male ,0301 basic medicine ,serology ,law.invention ,0302 clinical medicine ,law ,Surveys and Questionnaires ,Health care ,Epidemiology ,Medicine ,risk factors ,030212 general & internal medicine ,Young adult ,Biology (General) ,Asymptomatic Infections ,Incidence ,General Neuroscience ,Incidence (epidemiology) ,Age Factors ,General Medicine ,Middle Aged ,Intensive care unit ,Virus ,3. Good health ,Intensive Care Units ,Female ,medicine.symptom ,Coronavirus Infections ,Covid-19 ,Research Article ,Adult ,Risk ,medicine.medical_specialty ,Infectious Disease Transmission, Patient-to-Professional ,Adolescent ,QH301-705.5 ,Health Personnel ,Science ,Pneumonia, Viral ,030106 microbiology ,Asymptomatic ,General Biochemistry, Genetics and Molecular Biology ,Betacoronavirus ,Young Adult ,03 medical and health sciences ,Humans ,Hospitals, Teaching ,Pandemics ,Aged ,General Immunology and Microbiology ,business.industry ,SARS-CoV-2 ,healthcare workers ,Odds ratio ,United Kingdom ,Epidemiology and Global Health ,Family medicine ,symptoms ,Observational study ,business - Abstract
We conducted voluntary Covid-19 testing programmes for symptomatic and asymptomatic staff at a UK teaching hospital using naso-/oro-pharyngeal PCR testing and immunoassays for IgG antibodies. 1128/10,034 (11.2%) staff had evidence of Covid-19 at some time. Using questionnaire data provided on potential risk-factors, staff with a confirmed household contact were at greatest risk (adjusted odds ratio [aOR] 4.82 [95%CI 3.45–6.72]). Higher rates of Covid-19 were seen in staff working in Covid-19-facing areas (22.6% vs. 8.6% elsewhere) (aOR 2.47 [1.99–3.08]). Controlling for Covid-19-facing status, risks were heterogenous across the hospital, with higher rates in acute medicine (1.52 [1.07–2.16]) and sporadic outbreaks in areas with few or no Covid-19 patients. Covid-19 intensive care unit staff were relatively protected (0.44 [0.28–0.69]), likely by a bundle of PPE-related measures. Positive results were more likely in Black (1.66 [1.25–2.21]) and Asian (1.51 [1.28–1.77]) staff, independent of role or working location, and in porters and cleaners (2.06 [1.34–3.15]). more...
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- 2020
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4. Covalent Inhibitors of S100A4 Block the Formation of a Pro-Metastasis Non-Muscle Myosin 2A Complex.
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Giroud C, Szommer T, Coxon C, Monteiro O, Grimes T, Zarganes-Tzitzikas T, Christott T, Bennett J, Buchan K, Brennan PE, and Fedorov O
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- Humans, Cell Line, Tumor, Protein Binding, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Small Molecule Libraries chemical synthesis, Models, Molecular, Crystallography, X-Ray, S100 Calcium-Binding Protein A4 metabolism, S100 Calcium-Binding Protein A4 antagonists & inhibitors, Nonmuscle Myosin Type IIA antagonists & inhibitors, Nonmuscle Myosin Type IIA metabolism, Cell Movement drug effects
- Abstract
The S100 protein family functions as protein-protein interaction adaptors regulated by Ca
2+ binding. Formation of various S100 complexes plays a central role in cell functions, from calcium homeostasis to cell signaling, and is implicated in cell growth, migration, and tumorigenesis. We established a suite of biochemical and cellular assays for small molecule screening based on known S100 protein-protein interactions. From 25 human S100 proteins, we focused our attention on S100A4 because of its well-established role in cancer progression and metastasizes by interacting with nonmuscle myosin II (NMII). We identified several potent and selective inhibitors of this interaction and established the covalent nature of binding, confirmed by mass spectrometry and crystal structures. 5b showed on-target activity in cells and inhibition of cancer cell migration. The identified S100A4 inhibitors can serve as a basis for the discovery of new cancer drugs operating via a novel mode of action. more...- Published
- 2024
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5. Discovery of PFI-6, a small-molecule chemical probe for the YEATS domain of MLLT1 and MLLT3.
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Raux B, Buchan KA, Bennett J, Christott T, Dowling MS, Farnie G, Fedorov O, Gamble V, Gileadi C, Giroud C, Huber KVM, Korczynska M, Limberakis C, Narayanan A, Owen DR, Sáez LD, Stock IA, and Londregan AT more...
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- Humans, Protein Domains, Drug Discovery, Neoplasm Proteins metabolism, Transcription Factors metabolism, Nuclear Proteins metabolism, Histones metabolism
- Abstract
Epigenetic proteins containing YEATS domains (YD) are an emerging target class in drug discovery. Described herein are the discovery and characterization efforts associated with PFI-6, a new chemical probe for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). For hit identification, fragment-like mimetics of endogenous YD ligands (crotonylated histone-containing proteins), were synthesized via parallel medicinal chemistry (PMC) and screened for MLLT1 binding. Subsequent SAR studies led to iterative MLLT1/3 binding and selectivity improvements, culminating in the discovery of PFI-6. PFI-6 demonstrates good affinity and selectivity for MLLT1/3 vs. other human YD proteins (YEATS2/4) and engages MLLT3 in cells. Small-molecule X-ray co-crystal structures of two molecules, including PFI-6, bound to the YD of MLLT1/3 are also described. PFI-6 may be a useful tool molecule to better understand the biological effects associated with modulation of MLLT1/3., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.) more...
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- 2024
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6. Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4.
- Author
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Londregan AT, Aitmakhanova K, Bennett J, Byrnes LJ, Canterbury DP, Cheng X, Christott T, Clemens J, Coffey SB, Dias JM, Dowling MS, Farnie G, Fedorov O, Fennell KF, Gamble V, Gileadi C, Giroud C, Harris MR, Hollingshead BD, Huber K, Korczynska M, Lapham K, Loria PM, Narayanan A, Owen DR, Raux B, Sahasrabudhe PV, Ruggeri RB, Sáez LD, Stock IA, Thuma BA, Tsai A, and Varghese AE more...
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- Protein Domains, Acetylation, Epigenesis, Genetic, Gene Expression Regulation, Protein Processing, Post-Translational
- Abstract
A series of small-molecule YEATS4 binders have been discovered as part of an ongoing research effort to generate high-quality probe molecules for emerging and/or challenging epigenetic targets. Analogues such as 4d and 4e demonstrate excellent potency and selectivity for YEATS4 binding versus YEATS1,2,3 and exhibit good physical properties and in vitro safety profiles. A new X-ray crystal structure confirms direct binding of this chemical series to YEATS4 at the lysine acetylation recognition site of the YEATS domain. Multiple analogues engage YEATS4 with nanomolar potency in a whole-cell nanoluciferase bioluminescent resonance energy transfer assay. Rodent pharmacokinetic studies demonstrate the competency of several analogues as in vivo-capable binders. more...
- Published
- 2023
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7. Structural Insights into Interaction Mechanisms of Alternative Piperazine-urea YEATS Domain Binders in MLLT1.
- Author
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Ni X, Heidenreich D, Christott T, Bennett J, Moustakim M, Brennan PE, Fedorov O, Knapp S, and Chaikuad A
- Abstract
YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.) more...
- Published
- 2019
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8. A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function.
- Author
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Fagan V, Johansson C, Gileadi C, Monteiro O, Dunford JE, Nibhani R, Philpott M, Malzahn J, Wells G, Faram R, Cribbs AP, Halidi N, Li F, Chau I, Greschik H, Velupillai S, Allali-Hassani A, Bennett J, Christott T, Giroud C, Lewis AM, Huber KVM, Athanasou N, Bountra C, Jung M, Schüle R, Vedadi M, Arrowsmith C, Xiong Y, Jin J, Fedorov O, Farnie G, Brennan PE, and Oppermann U more...
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- Cell Cycle Proteins chemistry, Cell Line, Tumor, Crystallography, X-Ray, Humans, Microtubule-Associated Proteins chemistry, Phosphoproteins chemistry, Protein Conformation, Cell Cycle Proteins metabolism, Chromatin metabolism, Microtubule-Associated Proteins metabolism, Molecular Probes chemistry, Phosphoproteins metabolism, Tudor Domain
- Abstract
Modifications of histone tails, including lysine/arginine methylation, provide the basis of a "chromatin or histone code". Proteins that contain "reader" domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyllysine/arginine reader domains and was identified as a putative oncogene and transcriptional coactivator. Here we report a SPIN1 chemical probe inhibitor with low nanomolar in vitro activity, exquisite selectivity on a panel of methyl reader and writer proteins, and with submicromolar cellular activity. X-ray crystallography showed that this Tudor domain chemical probe simultaneously engages Tudor domains 1 and 2 via a bidentate binding mode. Small molecule inhibition and siRNA knockdown of SPIN1, as well as chemoproteomic studies, identified genes which are transcriptionally regulated by SPIN1 in squamous cell carcinoma and suggest that SPIN1 may have a role in cancer related inflammation and/or cancer metastasis. more...
- Published
- 2019
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9. Discovery of a Potent and Selective Fragment-like Inhibitor of Methyllysine Reader Protein Spindlin 1 (SPIN1).
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Xiong Y, Greschik H, Johansson C, Seifert L, Bacher J, Park KS, Babault N, Martini M, Fagan V, Li F, Chau I, Christott T, Dilworth D, Barsyte-Lovejoy D, Vedadi M, Arrowsmith CH, Brennan P, Fedorov O, Jung M, Farnie G, Liu J, Oppermann U, Schüle R, and Jin J more...
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- Chromatography, High Pressure Liquid, Crystallography, X-Ray, HEK293 Cells, Humans, Molecular Structure, Proton Magnetic Resonance Spectroscopy, Quinazolines chemistry, Cell Cycle Proteins antagonists & inhibitors, Drug Discovery, Microtubule-Associated Proteins antagonists & inhibitors, Phosphoproteins antagonists & inhibitors, Quinazolines pharmacology
- Abstract
By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective, and cell-active SPIN1 inhibitor, compound 3 (MS31). Compound 3 potently inhibited binding of trimethyllysine-containing peptides to SPIN1, displayed high binding affinity, was highly selective for SPIN1 over other epigenetic readers and writers, directly engaged SPIN1 in cells, and was not toxic to nontumorigenic cells. The crystal structure of the SPIN1-compound 3 complex indicated that it selectively binds tudor domain II of SPIN1. We also designed a structurally similar but inactive compound 4 (MS31N) as a negative control. Our results have demonstrated for the first time that potent, selective, and cell-active fragment-like inhibitors can be generated by targeting a single tudor domain. more...
- Published
- 2019
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10. Discovery of a Selective Inhibitor for the YEATS Domains of ENL/AF9.
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Christott T, Bennett J, Coxon C, Monteiro O, Giroud C, Beke V, Felce SL, Gamble V, Gileadi C, Poda G, Al-Awar R, Farnie G, and Fedorov O
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- Biophysical Phenomena, Drug Evaluation, Preclinical, HEK293 Cells, Histones metabolism, Humans, Inhibitory Concentration 50, Peptides metabolism, Protein Domains, Structure-Activity Relationship, Drug Discovery, Transcriptional Elongation Factors antagonists & inhibitors, Transcriptional Elongation Factors chemistry
- Abstract
Eleven-nineteen leukemia (ENL) contains an epigenetic reader domain (YEATS domain) that recognizes lysine acylation on histone 3 and facilitates transcription initiation and elongation through its interactions with the super elongation complex (SEC) and the histone methyl transferase DOT1L. Although it has been known for its role as a fusion protein in mixed lineage leukemia (MLL), overexpression of native ENL, and thus dysregulation of downstream genes in acute myeloid leukemia (AML), has recently been implicated as a driver of disease that is reliant on the epigenetic reader activity of the YEATS domain. We developed a peptide displacement assay (histone 3 tail with acylated lysine) and screened a small-molecule library totaling more than 24,000 compounds for their propensity to disrupt the YEATS domain-histone peptide binding. Among these, we identified a first-in-class dual inhibitor of ENL ( K
d = 745 ± 45 nM) and its paralog AF9 ( Kd = 523 ± 53 nM) and performed "SAR by catalog" with the aim of starting the development of a chemical probe for ENL. more...- Published
- 2019
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11. Discovery of an MLLT1/3 YEATS Domain Chemical Probe.
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Moustakim M, Christott T, Monteiro OP, Bennett J, Giroud C, Ward J, Rogers CM, Smith P, Panagakou I, Díaz-Sáez L, Felce SL, Gamble V, Gileadi C, Halidi N, Heidenreich D, Chaikuad A, Knapp S, Huber KVM, Farnie G, Heer J, Manevski N, Poda G, Al-Awar R, Dixon DJ, Brennan PE, and Fedorov O more...
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- Crystallography, X-Ray, Histones metabolism, Humans, Molecular Docking Simulation, Neoplasm Proteins metabolism, Nuclear Proteins metabolism, Protein Domains, Protein Interaction Maps drug effects, Small Molecule Libraries pharmacology, Transcription Factors metabolism, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins chemistry, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins chemistry, Small Molecule Libraries chemistry, Transcription Factors antagonists & inhibitors, Transcription Factors chemistry
- Abstract
YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine-binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small-molecule chemical probe, SGC-iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent and selective inhibitor of MLLT1/3-histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small-molecule X-ray co-crystal structures with the MLLT1 YD are also reported. This first-in-class probe molecule can be used to understand MLLT1/3-associated biology and the therapeutic potential of small-molecule YD inhibitors., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...
- Published
- 2018
- Full Text
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