Now showing items 1-18 of 18

    • 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 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 ...
    • 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 (2018-02-08)
      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 ...
    • The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design. 

      Couty, S; Westwood, IM; Kalusa, A; Cano, C; Travers, J; Boxall, K; Chow, CL; Burns, S; Schmitt, J; Pickard, L; Barillari, C; McAndrew, PC; Clarke, PA; Linardopoulos, S; Griffin, RJ; Aherne, GW; Raynaud, FI; Workman, P; Jones, K; van Montfort, RL (2013-10)
      The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we ...
    • 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 ...
    • In vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with PI3K inhibition in paediatric glioblastoma cells. 

      Al-Saffar, NMS; Agliano, A; Marshall, LV; Jackson, LE; Balarajah, G; Sidhu, J; Clarke, PA; Jones, C; Workman, P; Pearson, ADJ; Leach, MO (2017)
      Recent experimental data showed that the PI3K pathway contributes to resistance to temozolomide (TMZ) in paediatric glioblastoma and that this effect is reversed by combination treatment of TMZ with a PI3K inhibitor. Our ...
    • 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 ...
    • Inhibitors of cyclin-dependent kinases as cancer therapeutics. 

      Whittaker, SR; Mallinger, A; Workman, P; Clarke, PA (2017-05)
      Over the past two decades there has been a great deal of interest in the development of inhibitors of the cyclin-dependent kinases (CDKs). This attention initially stemmed from observations that different CDK isoforms have ...
    • 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 ...
    • 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. ...
    • Oncogenic RAC1 and NRAS drive resistance to endoplasmic reticulum stress through MEK/ERK signalling. 

      Bright, MD; Clarke, PA; Workman, P; Davies, FE (2018-04)
      Cancer cells are able to survive under conditions that cause endoplasmic reticulum stress (ER-stress), and can adapt to this stress by upregulating cell-survival signalling pathways and down-regulating apoptotic pathways. ...
    • Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control. 

      Pawlyn, C; Bright, MD; Buros, AF; Stein, CK; Walters, Z; Aronson, LI; Mirabella, F; Jones, JR; Kaiser, MF; Walker, BA; Jackson, GH; Clarke, PA; Bergsagel, PL; Workman, P; Chesi, M; Morgan, GJ; Davies, FE (2017-03-31)
      Myeloma is heterogeneous at the molecular level with subgroups of patients characterised by features of epigenetic dysregulation. Outcomes for myeloma patients have improved over the past few decades except for molecularly ...
    • 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 ...
    • Pediatric and adult glioblastoma radiosensitization induced by PI3K/mTOR inhibition causes early metabolic alterations detected by nuclear magnetic resonance spectroscopy. 

      Agliano, A; Balarajah, G; Ciobota, DM; Sidhu, J; Clarke, PA; Jones, C; Workman, P; Leach, MO; Al-Saffar, NMS (2017-07-18)
      Poor outcome for patients with glioblastomas is often associated with radioresistance. PI3K/mTOR pathway deregulation has been correlated with radioresistance; therefore, PI3K/mTOR inhibition could render tumors radiosensitive. ...
    • Restricting direct interaction of CDC37 with HSP90 does not compromise chaperoning of client proteins. 

      Smith, JR; de Billy, E; Hobbs, S; Powers, M; Prodromou, C; Pearl, L; Clarke, PA; Workman, P (2015-01)
      The HSP90 molecular chaperone plays a key role in the maturation, stability and activation of its clients, including many oncogenic proteins. Kinases are a substantial and important subset of clients requiring the key ...
    • RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses. 

      Dolly, SO; Gurden, MD; Drosopoulos, K; Clarke, P; de Bono, J; Kaye, S; Workman, P; Linardopoulos, S (2017-09-26)
      BACKGROUND: F-box and WD40 repeat domain-containing 7 (FBXW7) is an E3 ubiquitin ligase involved in the ubiquitination and degradation of multiple oncogenic substrates. The tumour suppressor function is frequently lost in ...
    • 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 ...