Now showing items 1-20 of 30

    • 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 ...
    • A Genome-scale CRISPR Screen Identifies the ERBB and mTOR Signaling Networks as Key Determinants of Response to PI3K Inhibition in Pancreatic Cancer. 

      Milton, CK; Self, AJ; Clarke, PA; Banerji, U; Piccioni, F; Root, DE; Whittaker, SR (2020-07)
      KRAS mutation is a key driver of pancreatic cancer and PI3K pathway activity is an additional requirement for Kras-induced tumorigenesis. Clinical trials of PI3K pathway inhibitors in pancreatic cancer have shown limited ...
    • A PI3K- and GTPase-independent Rac1-mTOR mechanism mediates MET-driven anchorage-independent cell growth but not migration. 

      Hervieu, A; Heuss, SF; Zhang, C; Barrow-McGee, R; Joffre, C; Ménard, L; Clarke, PA; Kermorgant, S (2020-06-23)
      Receptor tyrosine kinases (RTKs) are often overexpressed or mutated in cancers and drive tumor growth and metastasis. In the current model of RTK signaling, including that of MET, downstream phosphatidylinositol 3-kinase ...
    • 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 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 ...
    • CHK1 Inhibition Is Synthetically Lethal with Loss of B-Family DNA Polymerase Function in Human Lung and Colorectal Cancer Cells. 

      Rogers, RF; Walton, MI; Cherry, DL; Collins, I; Clarke, PA; Garrett, MD; Workman, P (2020-04)
      Checkpoint kinase 1 (CHK1) is a key mediator of the DNA damage response that regulates cell-cycle progression, DNA damage repair, and DNA replication. Small-molecule CHK1 inhibitors sensitize cancer cells to genotoxic ...
    • De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder. 

      Calpena, E; Hervieu, A; Kaserer, T; Swagemakers, SMA; Goos, JAC; Popoola, O; Ortiz-Ruiz, MJ; Barbaro-Dieber, T; Bownass, L; Brilstra, EH; Brimble, E; Foulds, N; Grebe, TA; Harder, AVE; Lees, MM; Monaghan, KG; Newbury-Ecob, RA; Ong, K-R; Osio, D; Reynoso Santos, FJ; Ruzhnikov, MRZ; Telegrafi, A; van Binsbergen, E; van Dooren, MF; Deciphering Developmental Disorders Study; van der Spek, PJ; Blagg, J; Twigg, SRF; Mathijssen, IMJ; Clarke, PA; Wilkie, AOM (2019-04)
      The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or ...
    • 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 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 ...
    • 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 ...
    • Evolution of kinase polypharmacology across HSP90 drug discovery. 

      Antolin, AA; Clarke, PA; Collins, I; Workman, P; Al-Lazikani, B (2021-05-27)
      Most small molecules interact with several target proteins but this polypharmacology is seldom comprehensively investigated or explicitly exploited during drug discovery. Here, we use computational and experimental methods ...
    • Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer. 

      Frame, S; Saladino, C; MacKay, C; Atrash, B; Sheldrake, P; McDonald, E; Clarke, PA; Workman, P; Blake, D; Zheleva, D (2020-01)
      Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed towards identification ...
    • 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 (2017-01)
      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 (2016-09)
      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 ...
    • 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 ...
    • Modulation of Biliary Cancer Chemo-Resistance Through MicroRNA-Mediated Rewiring of the Expansion of CD133+ Cells. 

      Carotenuto, P; Hedayat, S; Fassan, M; Cardinale, V; Lampis, A; Guzzardo, V; Vicentini, C; Scarpa, A; Cascione, L; Costantini, D; Carpino, G; Alvaro, D; Ghidini, M; Trevisani, F; Te Poele, R; Salati, M; Ventura, S; Vlachogiannis, G; Hahne, JC; Boulter, L; Forbes, SJ; Guest, RV; Cillo, U; Said-Huntingford, I; Begum, R; Smyth, E; Michalarea, V; Cunningham, D; Rimassa, L; Santoro, A; Roncalli, M; Kirkin, V; Clarke, P; Workman, P; Valeri, N; Braconi, C (2020-09-10)
      Background and aims Changes in single microRNA (miRNA) expression have been associated with chemo-resistance in biliary tract cancers (BTCs). However, a global assessment of the dynamic role of the microRNome has never ...
    • 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. ...