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  • Journal article
    Tate E, Lanyon-Hogg T, Ritzefeld M, Sefer L, Bickel JK, Rudolf A, Panyain N, Bineva-Todd G, OReilly N, Siebold C, Magee AIet al.,

    Acylation-coupled Lipophilic Induction of Polarisation (Acyl-cLIP): a Universal Assay for Lipid Transferase and Hydrolase Enzymes

    , Chemical Science, ISSN: 2041-6520
  • Journal article
    Storck Saha E, Morales Sanfrutos J, Serwa R, Panyain N, Lanyon-Hogg T, Tolmachova T, Ventimiglia L, Martin-Serrano J, Seabra M, Wojciak-Stothard B, Tate Eet al., 2019,

    Dual chemical probes enable quantitative system-wide analysis of protein prenylation and prenylation dynamics

    , Nature Chemistry, ISSN: 1755-4330

    Post-translational farnesylation or geranylgeranylation at a C-terminal cysteine residue regulates the localization and function of over 100 proteins, including the Ras isoforms, and is a therapeutic target in diseases including cancer and infection. Here, we report global and selective profiling of prenylated proteins in living cells enabled by the development of isoprenoid analogues YnF and YnGG in combination with quantitative chemical proteomics. Eighty prenylated proteins were identified in a single human cell line, 64 for the first time at endogenous abundance without metabolic perturbation. We further demonstrate that YnF and YnGG enable direct identification of post-translationally processed prenylated peptides, proteome-wide quantitative analysis of prenylation dynamics and alternative prenylation in response to four different prenyltransferase inhibitors, and quantification of defective Rab prenylation in a model of the retinal degenerative disease choroideremia.

  • Journal article
    Kallemeijn W, Lueg G, Faronato M, Hadavizadeh K, Goya Grocin A, Song O-R, Howell M, Dinnis C, Tate Eet al.,

    Validation and invalidation of chemical probes for the human N-myristoyltransferases

    , Cell Chemical Biology, ISSN: 2451-9456

    On-target, cell-active chemical probes are of fundamental importance in both chemical and cell biology, whereas the application of poorly-characterised probes often leads to invalid conclusions.Human N-myristoyltransferase (NMT) has attracted increasing interest as a target in cancer and infectious diseases; here we report an in-depth comparison of five compounds widely applied as human NMT inhibitors, using a combination of quantitative whole-proteome N-myristoylation profiling, biochemical enzyme assays, cytotoxicity, in-cell protein synthesis and cell cycle assays. We find that N-myristoylation is unaffected by 2-hydroxymyristic acid (100 μM), D-NMAPPD (30 μM) or Tris-DBA palladium (10 μM), with the latter compounds causing cytotoxicity through mechanisms unrelated to NMT. In contrast, drug-like inhibitors IMP-366 (DDD85646) and IMP-1088 delivered complete and specific inhibition of N-myristoylation in a range of cell lines at 1 μM and 100 nM, respectively. This study enables the selection of appropriate on-target probes for future studies and suggests the need for reassessment of previous studies which used off-target compounds.

  • Journal article
    Kaiser N, Mejuch T, Fedoryshchak R, Janning P, Tate EW, Waldmann Het al., 2019,

    Photoactivatable Myristic Acid Probes for UNC119-Cargo Interactions

    , CHEMBIOCHEM, Vol: 20, Pages: 134-139, ISSN: 1439-4227
  • Journal article
    Wang Z, Grosskurth SE, Cheung T, Petteruti P, Zhang J, Wang X, Wang W, Gharahdaghi F, Wu J, Su N, Howard RT, Mayo M, Widzowski D, Scott DA, Johannes JW, Lamb ML, Lawson D, Dry JR, Lyne PD, Tate EW, Zinda M, Mikule K, Fawell SE, Reimer C, Chen Het al.,

    Pharmacological inhibition of PARP6 triggers multipolar spindle formation and demonstrates therapeutic effects in breast cancer

    , Cancer Research, Vol: 78, Pages: 6691-6702, ISSN: 1538-7445

    PARP proteins represent a class of post-translational modification enzymes with diverse cellular functions. Targeting PARPs has proven to be efficacious clinically, but exploration of the therapeutic potential of PARP inhibition has been limited to targeting poly(ADP-ribose) generating PARP, including PARP1/2/3 and tankyrases. The cancer-related functions of mono(ADP-ribose) generating PARP, including PARP6, remain largely uncharacterized. Here, we report a novel therapeutic strategy targeting PARP6 using the first reported PARP6 inhibitors. By screening a collection of PARP compounds for their ability to induce mitotic defects, we uncovered a robust correlation between PARP6 inhibition and induction of multipolar spindle (MPS) formation, which was phenocopied by PARP6 knockdown. Treatment with AZ0108, a PARP6 inhibitor with a favorable pharmacokinetic profile, potently induced the MPS phenotype, leading to apoptosis in a subset of breast cancer cells in vitro and antitumor effects in vivo. In addition, Chk1 was identified as a specific substrate of PARP6 and was further confirmed by enzymatic assays and by mass spectrometry. Furthermore, when modification of Chk1 was inhibited with AZ0108 in breast cancer cells, we observed marked upregulation of p-S345 Chk1 accompanied by defects in mitotic signaling. Together, these results establish proof-of-concept antitumor efficacy through PARP6 inhibition and highlight a novel function of PARP6 in maintaining centrosome integrity via direct ADP-ribosylation of Chk1 and modulation of its activity.

  • Journal article
    De Vita E, Schuler P, Lovell S, Lohbeck J, Kullmann S, Rabinovich E, Sananes A, Hessling B, Hamon V, Papo N, Hess J, Tate EW, Gunkel N, Miller AKet al., 2018,

    Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity

    , JOURNAL OF MEDICINAL CHEMISTRY, Vol: 61, Pages: 8859-8874, ISSN: 0022-2623
  • Journal article
    Benns HJ, Tate EW, Child MA, 2018,

    Activity-Based Protein Profiling for the Study of Parasite Biology.

    , Curr Top Microbiol Immunol, Vol: 420, Pages: 155-174, ISSN: 0070-217X

    Parasites exist within most ecological niches, often transitioning through biologically and chemically complex host environments over the course of their parasitic life cycles. While the development of technologies for genetic engineering has revolutionised the field of functional genomics, parasites have historically been less amenable to such modification. In light of this, parasitologists have often been at the forefront of adopting new small-molecule technologies, repurposing drugs into biological tools and probes. Over the last decade, activity-based protein profiling (ABPP) has evolved into a powerful and versatile chemical proteomic platform for characterising the function of enzymes. Central to ABPP is the use of activity-based probes (ABPs), which covalently modify the active sites of enzyme classes ranging from serine hydrolases to glycosidases. The application of ABPP to cellular systems has contributed vastly to our knowledge on the fundamental biology of a diverse range of organisms and has facilitated the identification of potential drug targets in many pathogens. In this chapter, we provide a comprehensive review on the different forms of ABPP that have been successfully applied to parasite systems, and highlight key biological insights that have been enabled through their application.

  • Journal article
    Beard R, Stucki A, Schmitt M, Py G, Grundschober C, Gee A, Tate EWet al., 2018,

    Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs

    , Bioorganic and Medicinal Chemistry, Vol: 26, Pages: 3039-3045, ISSN: 0968-0896

    Oxytocin (OT) is an exciting potential therapeutic agent, but it is highly sensitive to modification and suffers extensive degradation at elevated temperature and in vivo. Here we report studies towards OT analogs with favorable selectivity, affinity and potency towards the oxytocin receptor (OTR), in addition to improving stability of the peptide by bridging the disulfide region with substituted dibromo-xylene analogs. We found a sensitive structure-activity relationship in which meta-cyclized analogs (dOTmeta) gave highest affinity (50 nM Ki), selectivity (34-fold), and agonist potency (34 nM EC50, 87-fold selectivity) towards OTR. Surprisingly, ortho-cyclized analogs demonstrated OTR and vasopressin V1a receptor subtype affinity (220 nM and 69 nM, respectively) and pharmacological activity (294 nM and 35 nM, respectively). V1a binding and selectivity for ortho-cyclized peptides could be improved 6-fold by substituting a neutral residue at position 8 with a basic amino acid, providing potent antagonists (14 nM IC50) that displayed no activation of the OTR. Furthermore, xylene-bridged analogs demonstrated increased stability compared to OT at elevated temperature, demonstrating promising therapeutic potential for these analogs which warrants further study.

  • Conference paper
    Riviere F, Dian C, Perez-Dorado I, Ritzefeld M, Shen J, Cota E, Meinnel T, Tate EW, Giglione Cet al., 2018,

    Mechanistic insight into HsNMT1-mediated acylation

    , Publisher: WILEY, Pages: 421-422, ISSN: 2211-5463
  • Conference paper
    Tate EW, 2018,

    Protein N terminal modifications: from chemical biology to drug discovery

    , Publisher: WILEY, Pages: 72-73, ISSN: 2211-5463

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