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  • Journal article
    De Vita E, Maneiro M, Tate EW, 2020,

    The Missing Link between (Un)druggable and Degradable KRAS

    , ACS CENTRAL SCIENCE, Vol: 6, Pages: 1281-1284, ISSN: 2374-7943
  • Journal article
    Benns HJ, Wincott CJ, Tate EW, Child MAet al., 2020,

    Activity- and reactivity-based proteomics: Recent technological advances and applications in drug discovery.

    , Current Opinion in Chemical Biology, Vol: 60, Pages: 20-29, ISSN: 1367-5931

    Activity-based protein profiling (ABPP) is recognized as a powerful and versatile chemoproteomic technology in drug discovery. Central to ABPP is the use of activity-based probes to report the activity of specific enzymes or reactivity of amino acid types in complex biological systems. Over the last two decades, ABPP has facilitated the identification of new drug targets and discovery of lead compounds in human and infectious disease. Furthermore, as part of a sustained global effort to illuminate the druggable proteome, the repertoire of target classes addressable with activity-based probes has vastly expanded in recent years. Here, we provide an overview of ABPP and summarise the major technological advances with an emphasis on probe development.
  • Journal article
    Bell AS, Yu Z, Hutton JA, Wright MH, Brannigan JA, Paape D, Roberts SM, Sutherell CL, Ritzefeld M, Wilkinson AJ, Smith DF, Leatherbarrow R, Tate EWet al., 2020,

    Novel thienopyrimidine inhibitors of Leishmania N-myristoyltransferase with on-target activity in intracellular amastigotes

    , Journal of Medicinal Chemistry, Vol: 14, Pages: 7740-7765, ISSN: 0022-2623

    The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with 12-15 million cases worldwide. Current therapeutic approaches are limited by toxicity, resistance and cost. N-Myristoyltransferase (NMT), an enzyme ubiquitous and essential in all eukaryotes, has been validated via genetic and pharmacological methods as a promising antileishmanial target. Here we describe a comprehensive structure activity relationship study of a thienopyrimidine series previously identified in a high throughput screen against Leishmania NMT, across 68 compounds in enzyme- and cell-based assay formats. Using a chemical tagging target engagement biomarker assay we identify the first inhibitor in this series with on-target NMT activity in leishmania parasites. Furthermore, crystal structure analyses of 12 derivatives in complex with Leishmania major NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (43), a compound with modest activity against L. donovani intracellular amastigotes and excellent selectivity (>660-fold) for Leishmania NMT over human NMTs.
  • Journal article
    Panyain N, Godinat A, Lanyon-Hogg T, Lachiondo-Ortega S, Will EJ, Soudy C, Mondal M, Mason K, Elkhalifa S, Smith L, Harrigan JA, Tate EWet al., 2020,

    Discovery of a potent and selective covalent inhibitor and activity-based probe for the deubiquitylating enzyme UCHL1, with anti-fibrotic activity

    , Journal of the American Chemical Society, Vol: 142, Pages: 12020-12026, ISSN: 0002-7863

    Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitylating enzyme which is proposed as a potential therapeutic target in neurodegeneration, cancer, and liver and lung fibrosis. Herein we report the discovery of the most potent and selective UCHL1 probe (IMP-1710) to date based on a covalent inhibitor scaffold and apply this probe to identify and quantify target proteins in intact human cells. IMP-1710 stereoselectively labels the catalytic cysteine of UCHL1 at low nanomolar concentration in cells. We further demonstrate that potent and selective UCHL1 inhibitors block pro-fibrotic responses in a cellular model of idiopathic pulmonary fibrosis, supporting the potential of UCHL1 as a potential therapeutic target in fibrotic diseases.
  • Journal article
    Alzahofi N, Welz T, Robinson CL, Page EL, Briggs DA, Stainthorp AK, Reekes J, Elbe DA, Straub F, Kallemeijn WW, Tate EW, Goff PS, Sviderskaya E, Cantero M, Montoliu L, Nedelec F, Miles AK, Bailly M, Kerkhoff E, Hume ANet al., 2020,

    Rab27a co-ordinates actin-dependent transport by controlling organelle-associated motors and track assembly proteins

    , NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723
  • Journal article
    Broncel M, Dominicus C, Vigetti L, Nofal SD, Bartlett EJ, Touquet B, Hunt A, Wallbank BA, Federico S, Matthews S, Young JC, Tate EW, Tardieux I, Treeck Met al., 2020,

    Profiling of myristoylation in Toxoplasma gondii reveals an N-myristoylated protein important for host cell penetration

    , ELIFE, Vol: 9, ISSN: 2050-084X
  • Journal article
    Maneiro M, Forte N, Shchepinova MM, Kounde CS, Chudasama V, Baker JR, Tate EWet al., 2020,

    Antibody–PROTAC conjugates enable HER2-dependent targeted protein degradation of BRD4

    , ACS Chemical Biology, Vol: 15, Pages: 1306-1312, ISSN: 1554-8929

    Targeting protein degradation with Proteolysis-Targeting Chimeras (PROTACs) is an area of great current interest in drug discovery. Nevertheless, although the high effectiveness of PROTACs against a wide variety of targets has been established, most degraders reported to date display limited intrinsic tissue selectivity and do not discriminate between cells of different types. Here, we describe a strategy for selective protein degradation in a specific cell type. We report the design and synthesis of a trastuzumab-PROTAC conjugate (Ab-PROTAC 3) in which E3 ligase-directed degrader activity is caged with an antibody linker which can be hydrolyzed following antibody–PROTAC internalization, releasing the active PROTAC and inducing catalytic protein degradation. We show that 3 selectively targets bromodomain-containing protein 4 (BRD4) for degradation only in HER2 positive breast cancer cell lines, while sparing HER2 negative cells. Using live cell confocal microscopy, we show internalization and lysosomal trafficking of the conjugate specifically in HER2 positive cells, leading to the release of active PROTAC in quantities sufficient to induce potent BRD4 degradation. These studies demonstrate proof-of-concept for tissue-specific BRD4 degradation, overcoming limitations of PROTAC selectivity, with significant potential for application to novel targets.
  • Journal article
    Saunders CN, Cota E, Baum J, Tate EWet al., 2020,

    Peptide probes for Plasmodium falciparum MyoA tail interacting protein (MTIP): exploring the druggability of the malaria parasite motor complex

    , ACS Chemical Biology, Vol: 15, Pages: 1313-1320, ISSN: 1554-8929

    Malaria remains an endemic tropical disease, and the emergence of Plasmodium falciparum parasites resistant to current front-line medicines means that new therapeutic targets are required. The Plasmodium glideosome is a multiprotein complex thought to be essential for efficient host red blood cell invasion. At its core is a myosin motor, Myosin A (MyoA), which provides most of the force required for parasite invasion. Here, we report the design and development of improved peptide-based probes for the anchor point of MyoA, the P. falciparum MyoA tail interacting protein (PfMTIP). These probes combine low nanomolar binding affinity with significantly enhanced cell penetration and demonstrable competitive target engagement with native PfMTIP through a combination of Western blot and chemical proteomics. These results provide new insights into the potential druggability of the MTIP/MyoA interaction and a basis for the future design of inhibitors.
  • Journal article
    Simoes BM, Santiago-Gomez A, Chiodo C, Moreira T, Conole D, Lovell S, Alferez D, Eyre R, Spence K, Sarmiento-Castro A, Kohler B, Morisset L, Lanzino M, Ando S, Marangoni E, Sims AH, Tate EW, Howell SJ, Clarke RBet al., 2020,

    Targeting STAT3 signaling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer

    , ONCOGENE, Vol: 39, Pages: 4896-4908, ISSN: 0950-9232
  • Journal article
    Shchepinova MM, Hanyaloglu AC, Frost GS, Tate EWet al., 2020,

    Chemical biology of noncanonical G protein-coupled receptor signaling: Toward advanced therapeutics

    , CURRENT OPINION IN CHEMICAL BIOLOGY, Vol: 56, Pages: 98-110, ISSN: 1367-5931

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