Now showing items 1-20 of 23

    • 2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19. 

      Mallinger, A; Schiemann, K; Rink, C; Sejberg, J; Honey, MA; Czodrowski, P; Stubbs, M; Poeschke, O; Busch, M; Schneider, R; Schwarz, D; Musil, D; Burke, R; Urbahns, K; Workman, P; Wienke, D; Clarke, PA; Raynaud, FI; Eccles, SA; Esdar, C; Rohdich, F; Blagg, J (2016-06)
      We demonstrate a designed scaffold-hop approach to the discovery of 2,8-disubstituted-1,6-naphthyridine- and 4,6-disubstituted-isoquinoline-based dual CDK8/19 ligands. Optimized compounds in both series exhibited rapid ...
    • 8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors. 

      Bavetsias, V; Lanigan, RM; Ruda, GF; Atrash, B; McLaughlin, MG; Tumber, A; Mok, NY; Le Bihan, Y-V; Dempster, S; Boxall, KJ; Jeganathan, F; Hatch, SB; Savitsky, P; Velupillai, S; Krojer, T; England, KS; Sejberg, J; Thai, C; Donovan, A; Pal, A; Scozzafava, G; Bennett, JM; Kawamura, A; Johansson, C; Szykowska, A; Gileadi, C; Burgess-Brown, NA; von Delft, F; Oppermann, U; Walters, Z; Shipley, J; Raynaud, FI; Westaway, SM; Prinjha, RK; Fedorov, O; Burke, R; Schofield, CJ; Westwood, IM; Bountra, C; Müller, S; van Montfort, RLM; Brennan, PE; Blagg, J (2016-02)
      We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a ...
    • A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. 

      Dale, T; Clarke, PA; Esdar, C; Waalboer, D; Adeniji-Popoola, O; Ortiz-Ruiz, M-J; Mallinger, A; Samant, RS; Czodrowski, P; Musil, D; Schwarz, D; Schneider, K; Stubbs, M; Ewan, K; Fraser, E; TePoele, R; Court, W; Box, G; Valenti, M; de Haven Brandon, A; Gowan, S; Rohdich, F; Raynaud, F; Schneider, R; Poeschke, O; Blaukat, A; Workman, P; Schiemann, K; Eccles, SA; Wienke, D; Blagg, J (2015-12)
      There is unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545, a small-molecule inhibitor of the WNT ...
    • Assessing histone demethylase inhibitors in cells: lessons learned. 

      Hatch, SB; Yapp, C; Montenegro, RC; Savitsky, P; Gamble, V; Tumber, A; Ruda, GF; Bavetsias, V; Fedorov, O; Atrash, B; Raynaud, F; Lanigan, R; Carmichael, L; Tomlin, K; Burke, R; Westaway, SM; Brown, JA; Prinjha, RK; Martinez, ED; Oppermann, U; Schofield, CJ; Bountra, C; Kawamura, A; Blagg, J; Brennan, PE; Rossanese, O; Müller, S (2017-01)
      Background Histone lysine demethylases (KDMs) are of interest as drug targets due to their regulatory roles in chromatin organization and their tight associations with diseases including cancer and mental disorders. The ...
    • Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases. 

      Clarke, PA; Ortiz-Ruiz, M-J; TePoele, R; Adeniji-Popoola, O; Box, G; Court, W; Czasch, S; El Bawab, S; Esdar, C; Ewan, K; Gowan, S; De Haven Brandon, A; Hewitt, P; Hobbs, SM; Kaufmann, W; Mallinger, A; Raynaud, F; Roe, T; Rohdich, F; Schiemann, K; Simon, S; Schneider, R; Valenti, M; Weigt, S; Blagg, J; Blaukat, A; Dale, TC; Eccles, SA; Hecht, S; Urbahns, K; Workman, P; Wienke, D (2016-12-09)
      Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility ...
    • C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays. 

      Le Bihan, Y-V; Lanigan, RM; Atrash, B; McLaughlin, MG; Velupillai, S; Malcolm, AG; England, KS; Ruda, GF; Mok, NY; Tumber, A; Tomlin, K; Saville, H; Shehu, E; McAndrew, C; Carmichael, L; Bennett, JM; Jeganathan, F; Eve, P; Donovan, A; Hayes, A; Wood, F; Raynaud, FI; Fedorov, O; Brennan, PE; Burke, R; van Montfort, RLM; Rossanese, OW; Blagg, J; Bavetsias, V (2019-09)
      Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit ...
    • Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy. 

      Faisal, A; Mak, GWY; Gurden, MD; Xavier, CPR; Anderhub, SJ; Innocenti, P; Westwood, IM; Naud, S; Hayes, A; Box, G; Valenti, MR; De Haven Brandon, AK; O'Fee, L; Schmitt, J; Woodward, HL; Burke, R; vanMontfort, RLM; Blagg, J; Raynaud, FI; Eccles, SA; Hoelder, S; Linardopoulos, S (2017-04)
      Background The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents ...
    • Characterization of Hedgehog Acyltransferase Inhibitors Identifies a Small Molecule Probe for Hedgehog Signaling by Cancer Cells. 

      Rodgers, UR; Lanyon-Hogg, T; Masumoto, N; Ritzefeld, M; Burke, R; Blagg, J; Magee, AI; Tate, EW (2016-12)
      The Sonic Hedgehog (Shh) signaling pathway plays a critical role during embryonic development and cancer progression. N-terminal palmitoylation of Shh by Hedgehog acyltransferase (Hhat) is essential for efficient signaling, ...
    • Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology. 

      Blagg, J; Workman, P (2017-07)
      Small-molecule chemical probes or tools have become progressively more important in recent years as valuable reagents to investigate fundamental biological mechanisms and processes causing disease, including cancer. Chemical ...
    • Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer. 

      Kaserer, T; Blagg, J (2018-11)
      The emergence of mutations that confer resistance to molecularly targeted therapeutics is dependent upon the effect of each mutation on drug affinity for the target protein, the clonal fitness of cells harboring the mutation, ...
    • Crystal structure of an Aurora-A mutant that mimics Aurora-B bound to MLN8054: insights into selectivity and drug design 

      Bavetsias, V; Blagg, J; Bayliss, R (2010)
      The production of selective protein kinase inhibitors is often frustrated by the similarity of the enzyme active sites. For this reason, it is challenging to design inhibitors that discriminate between the three Aurora ...
    • Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen. 

      Mallinger, A; Crumpler, S; Pichowicz, M; Waalboer, D; Stubbs, M; Adeniji-Popoola, O; Wood, B; Smith, E; Thai, C; Henley, AT; Georgi, K; Court, W; Hobbs, S; Box, G; Ortiz-Ruiz, M-J; Valenti, M; De Haven Brandon, A; TePoele, R; Leuthner, B; Workman, P; Aherne, W; Poeschke, O; Dale, T; Wienke, D; Esdar, C; Rohdich, F; Raynaud, F; Clarke, PA; Eccles, SA; Stieber, F; Schiemann, K; Blagg, J (2015-02-13)
      WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted ...
    • 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 ...
    • Donated chemical probes for open science. 

      Müller, S; Ackloo, S; Arrowsmith, CH; Bauser, M; Baryza, JL; Blagg, J; Böttcher, J; Bountra, C; Brown, PJ; Bunnage, ME; Carter, AJ; Damerell, D; Dötsch, V; Drewry, DH; Edwards, AM; Edwards, J; Elkins, JM; Fischer, C; Frye, SV; Gollner, A; Grimshaw, CE; IJzerman, A; Hanke, T; Hartung, IV; Hitchcock, S; Howe, T; Hughes, TV; Laufer, S; Li, VM; Liras, S; Marsden, BD; Matsui, H; Mathias, J; O'Hagan, RC; Owen, DR; Pande, V; Rauh, D; Rosenberg, SH; Roth, BL; Schneider, NS; Scholten, C; Singh Saikatendu, K; Simeonov, A; Takizawa, M; Tse, C; Thompson, PR; Treiber, DK; Viana, AY; Wells, CI; Willson, TM; Zuercher, WJ; Knapp, S; Mueller-Fahrnow, A (2018-04-20)
      Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and ...
    • Dynamic Equilibrium of the Aurora A Kinase Activation Loop Revealed by Single-Molecule Spectroscopy. 

      Gilburt, JAH; Sarkar, H; Sheldrake, P; Blagg, J; Ying, L; Dodson, CA (2017-09)
      The conformation of the activation loop (T-loop) of protein kinases underlies enzymatic activity and influences the binding of small-molecule inhibitors. By using single-molecule fluorescence spectroscopy, we have determined ...
    • Mapping the 3D structures of small molecule binding sites 

      Meyers, J; Brown, N; Blagg, J (BMC, 2016-12-06)
    • MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation. 

      Firth, NC; Atrash, B; Brown, N; Blagg, J (2015-06-09)
      We describe the development and application of an integrated, multiobjective optimization workflow (MOARF) for directed medicinal chemistry design. This workflow couples a rule-based molecular fragmentation scheme (SynDiR) ...
    • Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor. 

      Whittaker, SR; Barlow, C; Martin, MP; Mancusi, C; Wagner, S; Self, A; Barrie, E; Te Poele, R; Sharp, S; Brown, N; Wilson, S; Jackson, W; Fischer, PM; Clarke, PA; Walton, MI; McDonald, E; Blagg, J; Noble, M; Garrett, MD; Workman, P (2018-03)
      Deregulation of the cyclin-dependent kinases (CDKs) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDKs have garnered intense interest as therapeutic targets for the treatment of cancer. ...
    • 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)
      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 (<b>1</b>) and the ...
    • Pyrido[3,4-d]pyrimidin-4(3H)-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution. 

      Hayes, A; Mok, NY; Liu, M; Thai, C; Henley, AT; Atrash, B; Lanigan, RM; Sejberg, J; Le Bihan, Y-V; Bavetsias, V; Blagg, J; Raynaud, FI (2017-09)
      1. We have previously described C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as cell permeable inhibitors of the KDM4 and KDM5 subfamilies of JmjC histone lysine demethylases. 2. Although exemplar compound ...