Now showing items 25-44 of 94

    • Demonstrating In-Cell Target Engagement Using a Pirin Protein Degradation Probe (CCT367766). 

      Chessum, NEA; Sharp, SY; Caldwell, JJ; Pasqua, AE; Wilding, B; Colombano, G; Collins, I; Ozer, B; Richards, M; Rowlands, M; Stubbs, M; Burke, R; McAndrew, PC; Clarke, PA; Workman, P; Cheeseman, MD; Jones, K (2018-02)
      Demonstrating intracellular protein target engagement is an essential step in the development and progression of new chemical probes and potential small molecule therapeutics. However, this can be particularly challenging ...
    • Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen. 

      Cheeseman, MD; Chessum, NEA; Rye, CS; Pasqua, AE; Tucker, MJ; Wilding, B; Evans, LE; Lepri, S; Richards, M; Sharp, SY; Ali, S; Rowlands, M; O'Fee, L; Miah, A; Hayes, A; Henley, AT; Powers, M; Te Poele, R; De Billy, E; Pellegrino, L; Raynaud, F; Burke, R; van Montfort, RLM; Eccles, SA; Workman, P; Jones, K (2017-01)
      Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy for drug ...
    • Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19. 

      Mallinger, A; Schiemann, K; Rink, C; Stieber, F; Calderini, M; Crumpler, S; Stubbs, M; Adeniji-Popoola, O; Poeschke, O; Busch, M; Czodrowski, P; Musil, D; Schwarz, D; Ortiz-Ruiz, M-J; Schneider, R; Thai, C; Valenti, M; de Haven Brandon, A; Burke, R; Workman, P; Dale, T; Wienke, D; Clarke, PA; Esdar, C; Raynaud, FI; Eccles, SA; Rohdich, F; Blagg, J (2016-02)
      The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 ...
    • Dissecting mechanisms of resistance to targeted drug combination therapy in human colorectal cancer. 

      Clarke, PA; Roe, T; Swabey, K; Hobbs, SM; McAndrew, C; Tomlin, K; Westwood, I; Burke, R; van Montfort, R; Workman, P (2019-06)
      Genomic alterations in cancer cells result in vulnerabilities that clinicians can exploit using molecularly targeted drugs, guided by knowledge of the tumour genotype. However, the selective activity of these drugs exerts ...
    • DNA origami-based single-molecule force spectroscopy elucidates RNA Polymerase III pre-initiation complex stability. 

      Kramm, K; Schröder, T; Gouge, J; Vera, AM; Gupta, K; Heiss, FB; Liedl, T; Engel, C; Berger, I; Vannini, A; Tinnefeld, P; Grohmann, D (2020-06-05)
      The TATA-binding protein (TBP) and a transcription factor (TF) IIB-like factor are important constituents of all eukaryotic initiation complexes. The reason for the emergence and strict requirement of the additional ...
    • 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)
      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 evolutionary steering to induce collateral drug sensitivity in cancer. 

      Acar, A; Nichol, D; Fernandez-Mateos, J; Cresswell, GD; Barozzi, I; Hong, SP; Trahearn, N; Spiteri, I; Stubbs, M; Burke, R; Stewart, A; Caravagna, G; Werner, B; Vlachogiannis, G; Maley, CC; Magnani, L; Valeri, N; Banerji, U; Sottoriva, A (2020-04-21)
      Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another ...
    • 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, RLM; Jones, K (2016-05-11)
      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 ...
    • Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase. 

      Pollock, K; Liu, M; Zaleska, M; Meniconi, M; Pfuhl, M; Collins, I; Guettler, S (2019-12-13)
      The PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A number of these are implicated in ...
    • Functional studies of genome architectural proteins CTCF and ZNF143 

      Shen, R (2021-09-30)
      The genome architecture and gene transcription are interdependent. The way chromatin is packed within the nucleus controls when and how genes are expressed. A lot of chromatin interacting proteins are involved to ensure ...
    • 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 ...
    • Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer. 

      Woolston, A; Khan, K; Spain, G; Barber, LJ; Griffiths, B; Gonzalez-Exposito, R; Hornsteiner, L; Punta, M; Patil, Y; Newey, A; Mansukhani, S; Davies, MN; Furness, A; Sclafani, F; Peckitt, C; Jiménez, M; Kouvelakis, K; Ranftl, R; Begum, R; Rana, I; Thomas, J; Bryant, A; Quezada, S; Wotherspoon, A; Khan, N; Fotiadis, N; Marafioti, T; Powles, T; Lise, S; Calvo, F; Guettler, S; von Loga, K; Rao, S; Watkins, D; Starling, N; Chau, I; Sadanandam, A; Cunningham, D; Gerlinger, M (2019-07)
      Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS ...
    • High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers. 

      Anderhub, SJ; Mak, GW-Y; Gurden, MD; Faisal, A; Drosopoulos, K; Walsh, K; Woodward, HL; Innocenti, P; Westwood, IM; Naud, S; Hayes, A; Theofani, E; Filosto, S; Saville, H; Burke, R; van Montfort, RLM; Raynaud, FI; Blagg, J; Hoelder, S; Eccles, SA; Linardopoulos, S (2019-10)
      BOS172722 (CCT289346) is a highly potent, selective, and orally bioavailable inhibitor of spindle assembly checkpoint kinase MPS1. BOS172722 treatment alone induces significant sensitization to death, particularly in highly ...
    • High-resolution cryo-EM proteasome structures in drug development. 

      Morris, EP; da Fonseca, PCA (2017-06)
      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 ...
    • Human Condensin I and II Drive Extensive ATP-Dependent Compaction of Nucleosome-Bound DNA. 

      Kong, M; Cutts, EE; Pan, D; Beuron, F; Kaliyappan, T; Xue, C; Morris, EP; Musacchio, A; Vannini, A; Greene, EC (2020-07)
      Structural maintenance of chromosomes (SMC) complexes are essential for genome organization from bacteria to humans, but their mechanisms of action remain poorly understood. Here, we characterize human SMC complexes condensin ...
    • Hybrid Gene Origination Creates Human-Virus Chimeric Proteins during Infection. 

      Ho, JSY; Angel, M; Ma, Y; Sloan, E; Wang, G; Martinez-Romero, C; Alenquer, M; Roudko, V; Chung, L; Zheng, S; Chang, M; Fstkchyan, Y; Clohisey, S; Dinan, AM; Gibbs, J; Gifford, R; Shen, R; Gu, Q; Irigoyen, N; Campisi, L; Huang, C; Zhao, N; Jones, JD; van Knippenberg, I; Zhu, Z; Moshkina, N; Meyer, L; Noel, J; Peralta, Z; Rezelj, V; Kaake, R; Rosenberg, B; Wang, B; Wei, J; Paessler, S; Wise, HM; Johnson, J; Vannini, A; Amorim, MJ; Baillie, JK; Miraldi, ER; Benner, C; Brierley, I; Digard, P; Łuksza, M; Firth, AE; Krogan, N; Greenbaum, BD; MacLeod, MK; van Bakel, H; Garcìa-Sastre, A; Yewdell, JW; Hutchinson, E; Marazzi, I (2020-06-18)
      RNA viruses are a major human health threat. The life cycles of many highly pathogenic RNA viruses like influenza A virus (IAV) and Lassa virus depends on host mRNA, because viral polymerases cleave 5'-m7G-capped host ...
    • Identifying and Validating Tankyrase Binders and Substrates: A Candidate Approach. 

      Pollock, K; Ranes, M; Collins, I; Guettler, S (2017-01)
      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 (2016-09)
      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 ...
    • Investigating the phosphinic acid tripeptide mimetic DG013A as a tool compound inhibitor of the M1-aminopeptidase ERAP1. 

      Wilding, B; Pasqua, AE; E A Chessum, N; Pierrat, OA; Hahner, T; Tomlin, K; Shehu, E; Burke, R; Richards, GM; Whitton, B; Arwert, EN; Thapaliya, A; Salimraj, R; van Montfort, R; Skawinska, A; Hayes, A; Raynaud, F; Chopra, R; Jones, K; Newton, G; Cheeseman, MD
      ERAP1 is a zinc-dependent M1-aminopeptidase that trims lipophilic amino acids from the N-terminus of peptides. Owing to its importance in the processing of antigens and regulation of the adaptive immune response, dysregulation ...
    • Large Stokes shift fluorescence activation in an RNA aptamer by intermolecular proton transfer to guanine. 

      Mieczkowski, M; Steinmetzger, C; Bessi, I; Lenz, A-K; Schmiedel, A; Holzapfel, M; Lambert, C; Pena, V; Höbartner, C (2021-06-10)
      Fluorogenic RNA aptamers are synthetic functional RNAs that specifically bind and activate conditional fluorophores. The Chili RNA aptamer mimics large Stokes shift fluorescent proteins and exhibits high affinity for ...