Now showing items 1-20 of 44

    • 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 ...
    • 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. 

      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 (2019-01-08)
      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 (2019-02-07)
      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 ...
    • Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology. 

      Blagg, J; Workman, P (2017-07-10)
      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 (2018-02-08)
      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 ...
    • 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 (2016-08-01)
      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 (2017-01-12)
      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 ...
    • 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 ...
    • Drug discovery in advanced prostate cancer: translating biology into therapy. 

      Yap, TA; Smith, AD; Ferraldeschi, R; Al-Lazikani, B; Workman, P; de Bono, JS (2016-10)
      Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis and poses considerable therapeutic challenges. Recent genetic and technological advances have provided insights into prostate cancer biology ...
    • Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70. 

      Cheeseman, MD; Westwood, IM; Barbeau, O; Rowlands, M; Dobson, S; Jones, AM; Jeganathan, F; Burke, R; Kadi, N; Workman, P; Collins, I; van Montfort, RL; Jones, K (2016-05)
      HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought ...
    • 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, RL (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 ...
    • HSF1 Is Essential for Myeloma Cell Survival and A Promising Therapeutic Target. 

      Fok, JHL; Hedayat, S; Zhang, L; Aronson, LI; Mirabella, F; Pawlyn, C; Bright, MD; Wardell, CP; Keats, JJ; De Billy, E; Rye, CS; Chessum, NEA; Jones, K; Morgan, GJ; Eccles, SA; Workman, P; Davies, FE (2018-05-15)
      Purpose: Myeloma is a plasma cell malignancy characterized by the overproduction of immunoglobulin, and is therefore susceptible to therapies targeting protein homeostasis. We hypothesized that heat shock factor 1 (HSF1) ...
    • 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 ...