Now showing items 13-32 of 52

    • Evaluation of APOBEC3B Recognition Motifs by NMR Reveals Preferred Substrates. 

      Liu, M; Mallinger, A; Tortorici, M; Newbatt, Y; Richards, M; Mirza, A; van Montfort, RLM; Burke, R; Blagg, J; Kaserer, T (2018-09-21)
      APOBEC3B (A3B) deamination activity on ssDNA is considered a contributing factor to tumor heterogeneity and drug resistance in a number of human cancers. Despite its clinical impact, little is known about A3B ssDNA substrate ...
    • Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70. 

      Cheeseman, MD; Westwood, IM; Barbeau, O; Rowlands, M; Dobson, S; Jones, AM; Jeganathan, F; Burke, R; Kadi, N; Workman, P; Collins, I; van Montfort, RL; Jones, K (2016-05)
      HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought ...
    • A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms. 

      Jones, AM; Westwood, IM; Osborne, JD; Matthews, TP; Cheeseman, MD; Rowlands, MG; Jeganathan, F; Burke, R; Lee, D; Kadi, N; Liu, M; Richards, M; McAndrew, C; Yahya, N; Dobson, SE; Jones, K; Workman, P; Collins, I; van Montfort, RL (2016-10-06)
      The heat shock protein 70s (HSP70s) are molecular chaperones implicated in many cancers and of significant interest as targets for novel cancer therapies. Several HSP70 inhibitors have been reported, but because the majority ...
    • Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. 

      Pettitt, SJ; Krastev, DB; Brandsma, I; Dréan, A; Song, F; Aleksandrov, R; Harrell, MI; Menon, M; Brough, R; Campbell, J; Frankum, J; Ranes, M; Pemberton, HN; Rafiq, R; Fenwick, K; Swain, A; Guettler, S; Lee, J-M; Swisher, EM; Stoynov, S; Yusa, K; Ashworth, A; Lord, CJ (2018-05-10)
      Although PARP inhibitors (PARPi) target homologous recombination defective tumours, drug resistance frequently emerges, often via poorly understood mechanisms. Here, using genome-wide and high-density CRISPR-Cas9 ...
    • High-resolution cryo-EM proteasome structures in drug development. 

      Morris, EP; da Fonseca, PCA (2017-06-01)
      With the recent advances in biological structural electron microscopy (EM), protein structures can now be obtained by cryo-EM and single-particle analysis at resolutions that used to be achievable only by crystallographic ...
    • Identifying and Validating Tankyrase Binders and Substrates: A Candidate Approach. 

      Pollock, K; Ranes, M; Collins, I; Guettler, S (2017)
      The poly(ADP-ribose)polymerase (PARP) enzyme tankyrase (TNKS/ARTD5, TNKS2/ARTD6) uses its ankyrin repeat clusters (ARCs) to recognize degenerate peptide motifs in a wide range of proteins, thereby recruiting such proteins ...
    • Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors. 

      Vaughan, L; Clarke, PA; Barker, K; Chanthery, Y; Gustafson, CW; Tucker, E; Renshaw, J; Raynaud, F; Li, X; Burke, R; Jamin, Y; Robinson, SP; Pearson, A; Maira, M; Weiss, WA; Workman, P; Chesler, L (2016-07-12)
      MYC oncoproteins deliver a potent oncogenic stimulus in several human cancers, making them major targets for drug development, but efforts to deliver clinically practical therapeutics have not yet been realized. In childhood ...
    • An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine-56. 

      Pettinger, J; Le Bihan, Y-V; Widya, M; van Montfort, RLM; Jones, K; Cheeseman, MD (2017-03-20)
      The stress-inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells ...
    • Mechanism of selective recruitment of RNA polymerases II and III to snRNA gene promoters. 

      Dergai, O; Cousin, P; Gouge, J; Satia, K; Praz, V; Kuhlman, T; Lhôte, P; Vannini, A; Hernandez, N (2018-05-01)
      RNA polymerase II (Pol II) small nuclear RNA (snRNA) promoters and type 3 Pol III promoters have highly similar structures; both contain an interchangeable enhancer and "proximal sequence element" (PSE), which recruits the ...
    • MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma. 

      Lampis, A; Carotenuto, P; Vlachogiannis, G; Cascione, L; Hedayat, S; Burke, R; Clarke, P; Bosma, E; Simbolo, M; Scarpa, A; Yu, S; Cole, R; Smyth, E; Mateos, JF; Begum, R; Hezelova, B; Eltahir, Z; Wotherspoon, A; Fotiadis, N; Bali, MA; Nepal, C; Khan, K; Stubbs, M; Hahne, JC; Gasparini, P; Guzzardo, V; Croce, CM; Eccles, S; Fassan, M; Cunningham, D; Andersen, JB; Workman, P; Valeri, N; Braconi, C (2018-03)
      BACKGROUND & AIMS: Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small-molecule compounds that are active against CCAs. Levels of microRNA ...
    • MOB1 Mediated Phospho-recognition in the Core Mammalian Hippo Pathway. 

      Couzens, AL; Xiong, S; Knight, JDR; Mao, DY; Guettler, S; Picaud, S; Kurinov, I; Filippakopoulos, P; Sicheri, F; Gingras, A-C (2017-06)
      The Hippo tumor suppressor pathway regulates organ size and tissue homoeostasis in response to diverse signaling inputs. The core of the pathway consists of a short kinase cascade: MST1 and MST2 phosphorylate and activate ...
    • Molecular mechanisms of Bdp1 in TFIIIB assembly and RNA polymerase III transcription initiation. 

      Gouge, J; Guthertz, N; Kramm, K; Dergai, O; Abascal-Palacios, G; Satia, K; Cousin, P; Hernandez, N; Grohmann, D; Vannini, A (2017-07-25)
      Initiation of gene transcription by RNA polymerase (Pol) III requires the activity of TFIIIB, a complex formed by Brf1 (or Brf2), TBP (TATA-binding protein), and Bdp1. TFIIIB is required for recruitment of Pol III and to ...
    • Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737). 

      Osborne, JD; Matthews, TP; McHardy, T; Proisy, N; Cheung, KM; Lainchbury, M; Brown, N; Walton, MI; Eve, PD; Boxall, KJ; Hayes, A; Henley, AT; Valenti, MR; De Haven Brandon, AK; Box, G; Jamin, Y; Robinson, SP; Westwood, IM; van Montfort, RL; Leonard, PM; Lamers, MB; Reader, JC; Aherne, GW; Raynaud, FI; Eccles, SA; Garrett, MD; Collins, I (2016-06)
      Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy ...
    • Myosin and Actin Filaments in Muscle: Structures and Interactions. 

      Squire, JM; Paul, DM; Morris, EP (2017)
      In the last decade, improvements in electron microscopy and image processing have permitted significantly higher resolutions to be achieved (sometimes <1 nm) when studying isolated actin and myosin filaments. In the case ...
    • Nanostructures from Synthetic Genetic Polymers. 

      Taylor, AI; Beuron, F; Peak-Chew, SY; Morris, EP; Herdewijn, P; Holliger, P (2016-06)
      Nanoscale objects of increasing complexity can be constructed from DNA or RNA. However, the scope of potential applications could be enhanced by expanding beyond the moderate chemical diversity of natural nucleic acids. ...
    • New tricks for an old dog: Brf2-dependent RNA Polymerase III transcription in oxidative stress and cancer. 

      Gouge, J; Vannini, A (2018)
      Here, we discuss the role of Brf2, an RNA Polymerase III core transcription factor, as a master switch of the oxidative stress response. We highlight the interplay of Brf2 with the Nrf2/Keap1 pathway, as well as the role ...
    • Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. 

      Vlachogiannis, G; Hedayat, S; Vatsiou, A; Jamin, Y; Fernández-Mateos, J; Khan, K; Lampis, A; Eason, K; Huntingford, I; Burke, R; Rata, M; Koh, D-M; Tunariu, N; Collins, D; Hulkki-Wilson, S; Ragulan, C; Spiteri, I; Moorcraft, SY; Chau, I; Rao, S; Watkins, D; Fotiadis, N; Bali, M; Darvish-Damavandi, M; Lote, H; Eltahir, Z; Smyth, EC; Begum, R; Clarke, PA; Hahne, JC; Dowsett, M; de Bono, J; Workman, P; Sadanandam, A; Fassan, M; Sansom, OJ; Eccles, S; Starling, N; Braconi, C; Sottoriva, A; Robinson, SP; Cunningham, D; Valeri, N (2018-02-23)
      Patient-derived organoids (PDOs) have recently emerged as robust preclinical models; however, their potential to predict clinical outcomes in patients has remained unclear. We report on a living biobank of PDOs from ...
    • Privileged Structures and Polypharmacology within and between Protein Families. 

      Meyers, J; Chessum, NEA; Ali, S; Mok, NY; Wilding, B; Pasqua, AE; Rowlands, M; Tucker, MJ; Evans, LE; Rye, CS; O'Fee, L; Le Bihan, Y-V; Burke, R; Carter, M; Workman, P; Blagg, J; Brown, N; van Montfort, RLM; Jones, K; Cheeseman, MD (2018-12-13)
      Polypharmacology is often a key contributor to the efficacy of a drug, but is also a potential risk. We investigated two hits discovered via a cell-based phenotypic screen, the CDK9 inhibitor CCT250006 (1) and the pirin ...
    • Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach. 

      Innocenti, P; Woodward, HL; Solanki, S; Naud, S; Westwood, IM; Cronin, N; Hayes, A; Roberts, J; Henley, AT; Baker, R; Faisal, A; Mak, GW; Box, G; Valenti, M; De Haven Brandon, A; O'Fee, L; Saville, H; Schmitt, J; Matijssen, B; Burke, R; van Montfort, RL; Raynaud, FI; Eccles, SA; Linardopoulos, S; Blagg, J; Hoelder, S (2016-04-07)
      Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily ...
    • RavN is a member of a previously unrecognized group of Legionella pneumophila E3 ubiquitin ligases. 

      Lin, Y-H; Lucas, M; Evans, TR; Abascal-Palacios, G; Doms, AG; Beauchene, NA; Rojas, AL; Hierro, A; Machner, MP (2018-02)
      The eukaryotic ubiquitylation machinery catalyzes the covalent attachment of the small protein modifier ubiquitin to cellular target proteins in order to alter their fate. Microbial pathogens exploit this post-translational ...