Now showing items 1-20 of 66

    • 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 fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms. 

      Jones, AM; Westwood, IM; Osborne, JD; Matthews, TP; Cheeseman, MD; Rowlands, MG; Jeganathan, F; Burke, R; Lee, D; Kadi, N; Liu, M; Richards, M; McAndrew, C; Yahya, N; Dobson, SE; Jones, K; Workman, P; Collins, I; van Montfort, RLM (2016-10-06)
      The heat shock protein 70s (HSP70s) are molecular chaperones implicated in many cancers and of significant interest as targets for novel cancer therapies. Several HSP70 inhibitors have been reported, but because the majority ...
    • A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202;R-Roscovitine), administered twice daily for 7-days every 21 days. 

      Benson, C; White, J; De Bono, JS; O'Donnell, A; Raynaud, F; Cruickshank, C; McGrath, H; Frenz, L; Rose, F; Walton, M; Workman, P; Kaye, S
    • 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 ...
    • Can molecular biomarker-based patient selection in Phase I trials accelerate anticancer drug development? 

      Carden, CP; Sarker, D; Postel-Vinay, S; Yap, TA; Attard, G; Banerji, U; Garrett, MD; Thomas, GV; Workman, P; Kaye, SB; de Bono, JS (2010-02)
      Anticancer drug development remains slow, costly and inefficient. One way of addressing this might be the use of predictive biomarkers to select patients for Phase I/II trials. Such biomarkers, which predict response to ...
    • canSAR: update to the cancer translational research and drug discovery knowledgebase. 

      Mitsopoulos, C; Di Micco, P; Fernandez, EV; Dolciami, D; Holt, E; Mica, IL; Coker, EA; Tym, JE; Campbell, J; Che, KH; Ozer, B; Kannas, C; Antolin, AA; Workman, P; Al-Lazikani, B (2021-01)
      canSAR (http://cansar.icr.ac.uk) is the largest, public, freely available, integrative translational research and drug discovery knowledgebase for oncology. canSAR integrates vast multidisciplinary data from across genomic, ...
    • canSAR: update to the cancer translational research and drug discovery knowledgebase. 

      Coker, EA; Mitsopoulos, C; Tym, JE; Komianou, A; Kannas, C; Di Micco, P; Villasclaras Fernandez, E; Ozer, B; Antolin, AA; Workman, P; Al-Lazikani, B (2019-01)
      canSAR (http://cansar.icr.ac.uk) is a public, freely available, integrative translational research and drug discovery knowlegebase. canSAR informs researchers to help solve key bottlenecks in cancer translation and drug ...
    • Challenges to curing primary brain tumours. 

      Aldape, K; Brindle, KM; Chesler, L; Chopra, R; Gajjar, A; Gilbert, MR; Gottardo, N; Gutmann, DH; Hargrave, D; Holland, EC; Jones, DTW; Joyce, JA; Kearns, P; Kieran, MW; Mellinghoff, IK; Merchant, M; Pfister, SM; Pollard, SM; Ramaswamy, V; Rich, JN; Robinson, GW; Rowitch, DH; Sampson, JH; Taylor, MD; Workman, P; Gilbertson, RJ (2019-08)
      Despite decades of research, brain tumours remain among the deadliest of all forms of cancer. The ability of these tumours to resist almost all conventional and novel treatments relates, in part, to the unique cell-intrinsic ...
    • 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 ...
    • 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 ...
    • Combinatorial drug therapy for cancer in the post-genomic era. 

      Al-Lazikani, B; Banerji, U; Workman, P (2012-07-10)
      Over the past decade, whole genome sequencing and other 'omics' technologies have defined pathogenic driver mutations to which tumor cells are addicted. Such addictions, synthetic lethalities and other tumor vulnerabilities ...
    • Critical parameters in targeted drug development: the pharmacological audit trail. 

      Banerji, U; Workman, P (2016-08)
      The Pharmacological Audit Trail (PhAT) comprises a set of critical questions that need to be asked during discovery and development of an anticancer drug. Key aspects include: (1) defining a patient population; (2) ...
    • 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 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9. 

      Rye, CS; Chessum, NEA; Lamont, S; Pike, KG; Faulder, P; Demeritt, J; Kemmitt, P; Tucker, J; Zani, L; Cheeseman, MD; Isaac, R; Goodwin, L; Boros, J; Raynaud, F; Hayes, A; Henley, AT; de Billy, E; Lynch, CJ; Sharp, SY; Te Poele, R; Fee, LO; Foote, KM; Green, S; Workman, P; Jones, K (2016-08)
      Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents ...
    • 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, 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 ...
    • Distinctive Behaviors of Druggable Proteins in Cellular Networks. 

      Mitsopoulos, C; Schierz, AC; Workman, P; Al-Lazikani, B (2015-12-23)
      The interaction environment of a protein in a cellular network is important in defining the role that the protein plays in the system as a whole, and thus its potential suitability as a drug target. Despite the importance ...