Browsing ICR Divisions by author "Cheeseman, Matthew"
Now showing items 1-14 of 14
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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; et al. (NATURE PORTFOLIO, 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; et al. (WILEY-V C H VERLAG GMBH, 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 ... -
Demonstrating In-Cell Target Engagement Using a Pirin Protein Degradation Probe (CCT367766).
Chessum, NEA; Sharp, SY; Caldwell, JJ; Pasqua, AE; Wilding, B; et al. (AMER CHEMICAL SOC, 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 ... -
Determination of Ligand-Binding Affinity (Kd) Using Transverse Relaxation Rate (R2) in the Ligand-Observed 1H NMR Experiment and Applications to Fragment-Based Drug Discovery.
Liu, M; Mirza, A; McAndrew, PC; Thapaliya, A; Pierrat, OA; et al. (AMER CHEMICAL SOC, 2023-08-10)High hit rates from initial ligand-observed NMR screening can make it challenging to prioritize which hits to follow up, especially in cases where there are no available crystal structures of these hits bound to the target ... -
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; et al. (ROYAL SOC CHEMISTRY, 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; et al. (AMER CHEMICAL SOC, 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; et al. (AMER CHEMICAL SOC, 2016-05-26)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 ... -
HSF1 Pathway Inhibitor Clinical Candidate (CCT361814/NXP800) Developed from a Phenotypic Screen as a Potential Treatment for Refractory Ovarian Cancer and Other Malignancies.
Pasqua, AE; Sharp, SY; Chessum, NEA; Hayes, A; Pellegrino, L; et al. (AMER CHEMICAL SOC, 2023-04-27)CCT251236 1, a potent chemical probe, was previously developed from a cell-based phenotypic high-throughput screen (HTS) to discover inhibitors of transcription mediated by HSF1, a transcription factor that supports ... -
Investigating Apoptozole as a Chemical Probe for HSP70 Inhibition.
Evans, LE; Cheeseman, MD; Yahya, N; Jones, K (PUBLIC LIBRARY SCIENCE, 2015-10-12)The use of chemical tools to validate clinical targets has gained in popularity over recent years and the importance of understanding the activity, selectivity and mechanism of action of these compounds is well recognized. ... -
Investigating the phosphinic acid tripeptide mimetic DG013A as a tool compound inhibitor of the M1-aminopeptidase ERAP1.
Wilding, B; Pasqua, AE; E A Chessum, N; Pierrat, OA; Hahner, T; et al. (PERGAMON-ELSEVIER SCIENCE LTD, 2021-06-15)ERAP1 is a zinc-dependent M1-aminopeptidase that trims lipophilic amino acids from the N-terminus of peptides. Owing to its importance in the processing of antigens and regulation of the adaptive immune response, dysregulation ... -
Kinetic Optimization of Lysine-Targeting Covalent Inhibitors of HSP72.
Pettinger, J; Carter, M; Jones, K; Cheeseman, MD (AMER CHEMICAL SOC, 2019-12-26)The covalent inhibition mechanism of action, which overcomes competition with high-affinity, high-abundance substrates of challenging protein targets, can deliver effective chemical probes and drugs. The success of this ... -
Lysine-Targeting Covalent Inhibitors.
Pettinger, J; Jones, K; Cheeseman, MD (WILEY-V C H VERLAG GMBH, 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; et al. (AMER CHEMICAL SOC, 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 (ROYAL SOC CHEMISTRY, 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 ...