Now showing items 1-9 of 9

    • 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 ...
    • 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 ...
    • An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine-56. 

      Pettinger, J; Le Bihan, Y-V; Widya, M; van Montfort, RLM; Jones, K; Cheeseman, MD (2017-03-20)
      The stress-inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells ...
    • Lysine-Targeting Covalent Inhibitors. 

      Pettinger, J; Jones, K; Cheeseman, MD (2017-11-27)
      Targeted covalent inhibitors have gained widespread attention in drug discovery as a validated method to circumvent acquired resistance in oncology. This strategy exploits small-molecule/protein crystal structures to design ...
    • Privileged Structures and Polypharmacology within and between Protein Families. 

      Meyers, J; Chessum, NEA; Ali, S; Mok, NY; Wilding, B; Pasqua, AE; Rowlands, M; Tucker, MJ; Evans, LE; Rye, CS; O'Fee, L; Le Bihan, Y-V; Burke, R; Carter, M; Workman, P; Blagg, J; Brown, N; van Montfort, RLM; Jones, K; Cheeseman, MD (2018-12-13)
      Polypharmacology is often a key contributor to the efficacy of a drug, but is also a potential risk. We investigated two hits discovered via a cell-based phenotypic screen, the CDK9 inhibitor CCT250006 (1) and the pirin ...
    • Targeting secondary protein complexes in drug discovery: studying the druggability and chemical biology of the HSP70/BAG1 complex. 

      Evans, LE; Jones, K; Cheeseman, MD (2017-05-04)
      Proteins typically carry out their biological functions as multi-protein complexes, which can significantly affect the affinity of small-molecule inhibitors. HSP70 is an important target in oncology, so to study its chemical ...