Imperial College London

DrDavidMann

Faculty of Natural SciencesDepartment of Life Sciences

Reader in Cell Cycle Control
 
 
 
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Contact

 

+44 (0)20 7594 5302d.mann

 
 
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Location

 

605Sir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

109 results found

Watson L, Soliman TN, Davis K, Kelly J, Lockwood N, Yang X, Lynham S, Scott JD, Crossland V, McDonald NQ, Mann DJ, Armstrong A, Eggert U, Parker PJet al., 2021, Co-ordinated control of the Aurora B abscission checkpoint by PKC epsilon complex assembly, midbody recruitment and retention, BIOCHEMICAL JOURNAL, Vol: 478, Pages: 2247-2263, ISSN: 0264-6021

Journal article

Vilar Compte R, Summers P, Lewis B, Gonzalez-Garcia J, Porreca RM, Lim A, Cadinu P, Martin-Pintado N, Mann D, Edel J, Vannier JB, Kuimova M, Vilar Compte Ret al., 2021, Visualising G-quadruplex DNA dynamics in live cells by fluorescence lifetime imaging microscopy, Nature Communications, Vol: 12, ISSN: 2041-1723

Guanine rich regions of oligonucleotides fold into quadruple-stranded structures called G-quadruplexes (G4s). Increasing evidence suggests that these G4 structures form in vivo and play a crucial role in cellular processes. However, their direct observation in live cells remains a challenge. Here we demonstrate that a fluorescent probe (DAOTA-M2) in conjunction with fluorescence lifetime imaging microscopy (FLIM) can identify G4s within nuclei of live and fixed cells. We present a FLIM-based cellular assay to study the interaction of non-fluorescent small molecules with G4s and apply it to a wide range of drug candidates. We also demonstrate that DAOTA-M2 can be used to study G4 stability in live cells. Reduction of FancJ and RTEL1 expression in mammalian cells increases the DAOTA-M2 lifetime and therefore suggests an increased number of G4s in these cells, implying that FancJ and RTEL1 play a role in resolving G4 structures in cellulo.

Journal article

Craven GB, Armstrong A, Mann DJ, 2020, Quantitative Irreversible Tethering (qIT) for Target-directed Covalent Fragment Screening, BIO-PROTOCOL, Vol: 10

Journal article

Qin B, Craven GB, Hou P, Lu X, Child ES, Morgan RML, Armstrong A, Mann DJ, Cui Set al., 2020, Acrylamide Fragment Inhibitors that Induce Unprecedented Conformational Distortions in Enterovirus 71 3C and SARS-CoV-2 Main Protease

<jats:title>ABSTRACT</jats:title><jats:p>RNA viruses are critically dependent upon virally encoded proteases that cleave the viral polyproteins into functional mature proteins. Many of these proteases are structurally conserved with an essential catalytic cysteine and this offers the opportunity to irreversibly inhibit these enzymes with electrophilic small molecules. Here we describe the successful application of quantitative irreversible tethering (qIT) to identify acrylamide fragments that selectively target the active site cysteine of the 3C protease (3C<jats:sup>pro</jats:sup>) of Enterovirus 71, the causative agent of hand, foot and mouth disease in humans, altering the substrate binding region. Further, we effectively re-purpose these hits towards the main protease (M<jats:sup>pro</jats:sup>) of SARS-CoV-2 which shares the 3C-like fold as well as similar catalytic-triad. We demonstrate that the hit fragments covalently link to the catalytic cysteine of M<jats:sup>pro</jats:sup> to inhibit its activity. In addition, we provide the first demonstration that targeting the active site cysteine of M<jats:sup>pro</jats:sup> can also have profound allosteric effects, distorting secondary structures required for formation of the active dimeric unit of M<jats:sup>pro</jats:sup>. These new data provide novel mechanistic insights into the design of EV71 3C<jats:sup>pro</jats:sup> and SARS-CoV-2 M<jats:sup>pro</jats:sup> inhibitors and identify acrylamide-tagged pharmacophores for elaboration into more selective agents of therapeutic potential.</jats:p>

Journal article

Craven GB, Affron DP, Kösel T, Wong TLM, Jukes ZH, Liu C-T, Morgan RML, Armstrong A, Mann DJet al., 2020, Multiparameter kinetic analysis for covalent fragment optimization using quantitative irreversible tethering (qIT), ChemBioChem: a European journal of chemical biology, Vol: 21, Pages: 3417-3422, ISSN: 1439-4227

Covalent fragments are increasingly being implemented to develop chemical probes but the complex relationship between fragment structure and binding kinetics makes optimization uniquely challenging. We describe a new technique in covalent probe discovery that enables data driven optimization of covalent fragment potency and selectivity. This platform extends beyond the existing methods for covalent fragment hit identification by facilitating rapid multiparameter kinetic analysis of covalent structure-activity relationships through simultaneous determination of Ki, kinact and intrinsic reactivity. We apply this approach to develop novel probes against electrophile sensitive kinases and showcase how multiparameter kinetic analysis enabled a successful fragment merging strategy.

Journal article

Vilar R, Ruehl CL, Lim AHM, Kench T, Mann DJet al., 2019, An octahedral cobalt(III) complex with axial NH3 ligands that templates and selectively stabilises G-quadruplex DNA, Chemistry - A European Journal, Vol: 25, Pages: 9691-9700, ISSN: 0947-6539

Guanine-rich sequences of DNA are known to readily fold into tetra-stranded helical structures known as G-quadruplexes (G4). Due to their biological relevance, G4s are potential anticancer drug targets and therefore there is significant interest in molecules with high affinity for these structures. Most G4 binders are polyaromatic planar compounds which π-π stack on the G4's guanine tetrad. However, many of these compounds are not very selective since they can also intercalate into duplex DNA. Herein we report a new class of binder based on an octahedral cobalt(III) complex that binds to G4 via a different mode involving hydrogen-bonding, electrostatic interactions and π-π stacking. We show that this new compound binds selectivity to G4 over duplex DNA (particularly to the G-rich sequence of the c-myc promoter). This new octahedral complex also has the ability to template he formation of G4 DNA from the unfolded sequence. Finally, we show that upon binding to G4, the complex prevents helicase Pif1-p from unfolding the c-myc G4 structure.

Journal article

Craven G, Affron D, Raymond P, Mann D, Armstrong Aet al., 2019, Vinyl sulfonamide synthesis for irreversible tethering via a novel α-selenoether protection strategy, MedChemComm, Vol: 10, Pages: 158-163, ISSN: 2040-2503

Vinyl sulfonamides are valuable electrophiles for targeted protein modification and inhibition. We describe a novel approach to the synthesis of terminal vinyl sulfonamides which uses mild oxidative conditions to induce elimination of an α-selenoether masking group. The method complements traditional synthetic approaches and typically yields vinyl sulfonamides in high purity after aqueous work-up without requiring column chromatography of the final electrophilic product. The methodology is applied to the synthesis of covalent fragments for use in irreversible protein tethering and crucially enables the attachment of diverse fragments to the vinyl sulfonamide warhead via a chemical linker. Using thymidylate synthase as a model system, ethylene glycol is identified as an effective linker for irreversible protein tethering.

Journal article

Craven G, Affron D, Allen C, Matthies S, Greener J, Morgan R, Tate E, Armstrong A, Mann Det al., 2018, High-throughput kinetic analysis for target-directed covalent ligand discovery, Angewandte Chemie International Edition, Vol: 57, Pages: 5257-5261, ISSN: 1433-7851

Cysteine-­reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high-­quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan-­reactive compounds. Here we describe quantitative irreversible tethering(qIT), a general method for screening cysteine-­reactive small moleculesbased upon the maximization of kinetic selectivity. We apply this method prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2-­selective allosteric (type IV) kinase inhibitor whose novel mode-­of-­action could be exploited therapeutically.

Journal article

Craven GB, Affron DP, Allen CE, Matthies S, Greener JG, Morgan RML, Tate EW, Armstrong A, Mann DJet al., 2018, High-throughput kinetic analysis for target-directed covalent ligand discovery, Angewandte Chemie, Vol: 130, Pages: 5355-5359, ISSN: 0044-8249

Cysteine‐reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high‐quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan‐reactive compounds. Quantitative irreversible tethering (qIT), a general method for screening cysteine‐reactive small molecules based upon the maximization of kinetic selectivity, is described. This method was applied prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2‐selective allosteric (type IV) kinase inhibitor whose novel mode‐of‐action could be exploited therapeutically.

Journal article

Mann D, Armstrong A, Craven G, Matthies Set al., 2018, (WO2018033753) ASSAY, PCT/GB2017/052456

The present invention relates to a method of measuring the rate of reaction between a target molecule and a ligand candidate, ligands of interest identified according to this method and drugs developed from such ligands. The present invention also relates to a method of measuring the rate of reaction between a thiol and a molecule capable of reacting with said thiol.

Patent

Thinon E, Morales Sanfrutos J, Mann D, Tate EWet al., 2016, N-Myristoyltransferase Inhibition Induces ER-Stress, Cell Cycle Arrest, and Apoptosis in Cancer Cells, ACS Chemical Biology, Vol: 11, Pages: 2165-2176, ISSN: 1554-8937

N-Myristoyltransferase (NMT) covalently attaches a C14-fatty acid to the N-terminal glycine of proteins and has been proposed as a therapeutic target in cancer. We have recently shown that selective NMT inhibition leads to dose-responsive loss of N-myristoylation on more than 100 protein targets in cells, and cytotoxicity in cancer cells. N-myristoylation lies upstream of multiple pro-proliferative and oncogenic pathways, but to date the complex substrate specificity of NMT has limited determination of which diseases are most likely to respond to a selective NMT inhibitor. We describe here the phenotype of NMT inhibition in HeLa cells, and show that cells die through apoptosis following or concurrent with accumulation in G1 phase. We used quantitative proteomics to map protein expression changes for more than 2700 proteins in response to treatment with an NMT inhibitor in HeLa cells, and observed down-regulation of proteins involved in cell cycle regulation, and up-regulation of proteins involved in the endoplasmic reticulum stress and unfolded protein response, with similar results in breast (MCF-7, MDA-MB-231) and colon (HCT116) cancer cell lines. This study describes the cellular response to NMT inhibition at the proteome level, and provides a starting point for selective targeting of specific diseases with NMT inhibitors, potentially in combination with other targeted agents.

Journal article

Tretina K, Gotia HT, Mann DJ, Silva JCet al., 2015, Theileria-transformed bovine leukocytes have cancer hallmarks, TRENDS IN PARASITOLOGY, Vol: 31, Pages: 306-314, ISSN: 1471-4922

Journal article

Wang N, She Z, Lin Y-C, Martic S, Mann DJ, Kraatz H-Bet al., 2015, Clickable 5 '-gamma-Ferrocenyl Adenosine Triphosphate Bioconjugates in Kinase-Catalyzed Phosphorylations, CHEMISTRY-A EUROPEAN JOURNAL, Vol: 21, Pages: 4988-4999, ISSN: 0947-6539

Journal article

Stafford VS, Suntharalingam K, Shivalingam A, White AJP, Mann DJ, Vilar Ret al., 2014, Syntheses of polypyridyl metal complexes and studies of their interaction with quadruplex DNA, Dalton Transactions, Vol: 44, Pages: 3686-3700, ISSN: 1477-9226

A series of mono- and bi-metallic metal complexes (with CuII, PtII and ZnII) with substituted polypyridylligands have been prepared and their binding affinities towards quadruplex (c-Myc and human telomeric)and duplex DNA (ds26 and calf thymus) determined using fluorescent indicator displacement (FID) assaysand UV/vis spectroscopic titrations. These studies have shown that the number of aromatic rings andnumber/position of cyclic amine substituents on the ligands, play an important role in defining the DNAbinding abilities of the resulting metal complexes. We also show that bi-metallic complexes preparedusing a novel terpyridine-cyclen ligand have higher affinity towards G-quadruplex DNA as compared totheir mono-metallic counterparts. Cytotoxicity assays were carried out for all the new complexes againstan osteosarcoma cancer cell line (U2OS) as well as a normal fibroblast cell line (GM05757). Several ofthese compounds displayed cytotoxicity similar to that of cisplatin.

Journal article

Thinon E, Serwa RA, Broncel M, Brannigan JA, Brassat U, Wright MH, Heal WP, Wilkinson AJ, Mann DJ, Tate EWet al., 2014, Global profiling of co- and post-translationally N-myristoylated proteomes in human cells, Nature Communications, Vol: 5, Pages: 1-13, ISSN: 2041-1723

Protein N-myristoylation is a ubiquitous co- and post-translational modification that has been implicated in the development and progression of a range of human diseases. Here, we report the global N-myristoylated proteome in human cells determined using quantitative chemical proteomics combined with potent and specific human N-myristoyltransferase (NMT) inhibition. Global quantification of N-myristoylation during normal growth or apoptosis allowed the identification of >100 N-myristoylated proteins, >95% of which are identified for the first time at endogenous levels. Furthermore, quantitative dose response for inhibition of N-myristoylation is determined for >70 substrates simultaneously across the proteome. Small-molecule inhibition through a conserved substrate-binding pocket is also demonstrated by solving the crystal structures of inhibitor-bound NMT1 and NMT2. The presented data substantially expand the known repertoire of co- and post-translational N-myristoylation in addition to validating tools for the pharmacological inhibition of NMT in living cells.

Journal article

Sala R, Quang-De N, Patel CBK, Mann D, Steinke JHG, Vilar R, Aboagye EOet al., 2014, Phosphorylation Status of Thymidine Kinase 1 Following Antiproliferative Drug Treatment Mediates 3 '-Deoxy-3 '-[F-18]-Fluorothymidine Cellular Retention, PLOS ONE, Vol: 9, ISSN: 1932-6203

Journal article

Smith DE, Yong K, Mann DJ, 2014, Dysregulation of cyclin D expression in multiple myeloma alters the cell cycle response to DNA damage, 54th Annual Scientific Meeting of the British-Society-for-Haematology, Publisher: WILEY-BLACKWELL, Pages: 49-49, ISSN: 0007-1048

Conference paper

Wright MH, Clough B, Rackham MD, Kaveri R, Brannigan J, Grainger M, Moss DK, Bottrill AR, Heal WP, Broncel M, Serwa RA, Brady D, Mann DJ, Leatherbarrow RJ, Tewari R, Wilkinson AJ, Holder AA, Tate EWet al., 2013, Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach, Nature Chemistry, Vol: 6, Pages: 112-121, ISSN: 1755-4349

Malaria is an infectious disease caused by parasites of the genus Plasmodium, which leads to approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase, which catalyses the attachment of the fatty acid myristate to protein substrates (N-myristoylation). Here, we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small-molecule N-myristoyltransferase inhibitors. We demonstrate that N-myristoyltransferase is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for the development of new antimalarials targeting N-myristoyltransferase.

Journal article

Yelina NE, Ziolkowski PA, Miller N, Zhao X, Kelly KA, Munoz DF, Mann DJ, Copenhaver GP, Henderson IRet al., 2013, High-throughput analysis of meiotic crossover frequency and interference via flow cytometry of fluorescent pollen in Arabidopsis thaliana, NATURE PROTOCOLS, Vol: 8, Pages: 2119-2134, ISSN: 1754-2189

Journal article

Eccles SA, Aboagye EO, Ali S, Anderson AS, Armes J, Berditchevski F, Blaydes JP, Brennan K, Brown NJ, Bryant HE, Bundred NJ, Burchell JM, Campbell AM, Carroll JS, Clarke RB, Coles CE, Cook GJR, Cox A, Curtin NJ, Dekker LV, dos Santos Silva I, Duffy SW, Easton DF, Eccles DM, Edwards DR, Edwards J, Evans D, Fenlon DF, Flanagan JM, Foster C, Gallagher WM, Garcia-Closas M, Gee JMW, Gescher AJ, Goh V, Groves AM, Harvey AJ, Harvie M, Hennessy BT, Hiscox S, Holen I, Howell SJ, Howell A, Hubbard G, Hulbert-Williams N, Hunter MS, Jasani B, Jones LJ, Key TJ, Kirwan CC, Kong A, Kunkler IH, Langdon SP, Leach MO, Mann DJ, Marshall JF, Martin L, Martin SG, Macdougall JE, Miles DW, Miller WR, Morris JR, Moss SM, Mullan P, Natrajan R, OConnor JPB, OConnor R, Palmieri C, Pharoah PDP, Rakha EA, Reed E, Robinson SP, Sahai E, Saxton JM, Schmid P, Smalley MJ, Speirs V, Stein R, Stingl J, Streuli CH, Tutt ANJ, Velikova G, Walker RA, Watson CJ, Williams KJ, Young LS, Thompson AMet al., 2013, Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer, Breast Cancer Research, Vol: 15, Pages: R-R, ISSN: 1465-542X

IntroductionBreast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.MethodsMore than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.ResultsThe 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease

Journal article

Collins JC, Armstrong A, Chapman KL, Cordingley HC, Jaxa-Chamiec AA, Judd KE, Mann DJ, Scott KA, Tralau-Stewart CJ, Low CMRet al., 2013, Prospective use of molecular field points in ligand-based virtual screening: efficient identification of new reversible Cdc25 inhibitors, MEDCHEMCOMM, Vol: 4, Pages: 1148-1155, ISSN: 2040-2503

Journal article

Byrne SL, Yaliraki SN, Barahona M, Mann DJet al., 2013, Stability analysis of protein kinases, 9th European-Biophysical-Societies-Association Congress, Publisher: SPRINGER, Pages: S174-S174, ISSN: 0175-7571

Conference paper

Suntharalingam K, Mendoza O, Duarte AA, Mann DJ, Vilar Ret al., 2013, A platinum complex that binds non-covalently to DNA and induces cell death via a different mechanism than cisplatin, METALLOMICS, Vol: 5, Pages: 514-523, ISSN: 1756-5901

Journal article

Nonoo RH, Armstrong A, Mann DJ, 2012, Kinetic Template-Guided Tethering of Fragments, CHEMMEDCHEM, Vol: 7, Pages: 2082-2086, ISSN: 1860-7179

Journal article

Suntharalingam K, Hunt DJ, Duarte AA, White AJP, Mann DJ, Vilar Ret al., 2012, A Tri-copper(II) Complex Displaying DNA-Cleaving Properties and Antiproliferative Activity against Cancer Cells, CHEMISTRY-A EUROPEAN JOURNAL, Vol: 18, Pages: 15133-15141, ISSN: 0947-6539

Journal article

Mak LH, Knott J, Scott KA, Scott C, Whyte GF, Ye Y, Mann DJ, Ces O, Stivers J, Woscholski Ret al., 2012, Arylstibonic acids are potent and isoform-selective inhibitors of Cdc25a and Cdc25b phosphatases, BIOORGANIC & MEDICINAL CHEMISTRY, Vol: 20, Pages: 4371-4376, ISSN: 0968-0896

Journal article

Ohtani N, Takahashi A, Mann DJ, Hara Eet al., 2012, Cellular senescence: a double-edged sword in the fight against cancer, EXPERIMENTAL DERMATOLOGY, Vol: 21, Pages: 1-4, ISSN: 0906-6705

Journal article

Child ES, Georgiades SN, Rose KN, Stafford VS, Patel CBK, Steinke JHG, Mann DJ, Vilar Ret al., 2011, Inhibition of mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase 2 (Cdk2) by platinum(II) phenanthroline complexes., J Chem Biol, Vol: 4, Pages: 159-165

UNLABELLED: Inhibition of protein kinases in the fight against disease remains a constant challenge for medicinal chemists, who have screened multitudes of predominantly planar organic scaffolds, natural and synthetic, to identify potent-albeit not always selective-kinase inhibitors. Herein, in an effort to investigate the potential biological utility of metal-based compounds as inhibitors against the cancer-relevant targets mitogen-activated protein kinase and cyclin-dependent kinase 2, we explore various parameters in planar platinum(II) complexes with substituted phenanthroline ligands and aliphatic diamine chelate co-ligands, to identify combinations that yield promising inhibitory activity. The individual ligands' steric requirements as well as their pattern of hydrogen bond donors/acceptors appear to alter inhibitory potency when modulated. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12154-011-0059-5) contains supplementary material, which is available to authorized users.

Journal article

Lee SE, Elphick LM, Kramer HB, Jones AME, Child ES, Anderson AA, Bonnac L, Suwaki N, Kessler BM, Gouverneur V, Mann DJet al., 2011, The Chemoselective One-Step Alkylation and Isolation of Thiophosphorylated Cdk2 Substrates in the Presence of Native Cysteine, CHEMBIOCHEM, Vol: 12, Pages: 633-640, ISSN: 1439-4227

Journal article

Brooke GN, Culley RL, Dart DA, Mann DJ, Gaughan L, McCracken SR, Robson CN, Spencer-Dene B, Gamble SC, Powell SM, Wait R, Waxman J, Walker MM, Bevan CLet al., 2011, FUS/TLS Is a Novel Mediator of Androgen-Dependent Cell-Cycle Progression and Prostate Cancer Growth, CANCER RESEARCH, Vol: 71, Pages: 914-924, ISSN: 0008-5472

Journal article

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