Now showing items 1-17 of 17

    • 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 ...
    • 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)
      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 ...
    • 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 (2017-04-25)
      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 ...
    • 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
      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
      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 (2018-08-17)
      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 ...
    • 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 (2017-09-11)
      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 ...
    • 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 ...
    • Mapping the 3D structures of small molecule binding sites 

      Meyers, J; Brown, N; Blagg, J (2016-12-06)
    • 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. ...
    • 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, YV; Bavetsias, V; Blagg, J; Raynaud, FI (2016-09-12)
      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 1 ...
    • 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 ...
    • 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, MJ; 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 ...
    • Structure-based optimization of potent, selective and orally bioavailable CDK8 inhibitors discovered by high throughput screening. 

      Czodrowski, P; Mallinger, A; Wienke, D; Esdar, C; Poeschke, O; Busch, M; Rohdich, F; Eccles, SA; Ortiz Ruiz, MJ; Schneider, R; Raynaud, FI; Clarke, PA; Musil, D; Schwarz, D; Dale, TC; Urbahns, K; Blagg, J; Schiemann, K (2016-08-04)
      The Mediator complex-associated cyclin dependent kinase CDK8 regulates beta-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the ...
    • Targeting Androgen Receptor Aberrations in Castration-Resistant Prostate Cancer. 

      Sharp, A; Welti, J; Blagg, J; de Bono, JS (2016-09)
      Androgen receptor (AR) splice variants (SV) have been implicated in the development of metastatic castration-resistant prostate cancer and resistance to AR targeting therapies, including abiraterone and enzalutamide. Agents ...