Browsing by author "Jones, Keith"
Now showing items 1-13 of 13
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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 ... -
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 Is Essential for Myeloma Cell Survival and A Promising Therapeutic Target.
Fok, JHL; Hedayat, S; Zhang, L; Aronson, LI; Mirabella, F; et al. (AMER ASSOC CANCER RESEARCH, 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) ... -
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. ... -
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 ... -
Synthesis and profiling of a 3-aminopyridin-2-one-based kinase targeted fragment library: Identification of 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one scaffold for monopolar spindle 1 (MPS1) and Aurora kinases inhibition.
Fearon, D; Westwood, IM; van Montfort, RLM; Bayliss, R; Jones, K; et al. (PERGAMON-ELSEVIER SCIENCE LTD, 2018-07-15)Screening a 3-aminopyridin-2-one based fragment library against a 26-kinase panel representative of the human kinome identified 3-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one (2) and 3-amino-5-(pyridin-4-yl)pyridi ... -
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 ... -
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; et al. (IMPACT JOURNALS LLC, 2013-08-25)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 ...