Matthew D. Cheeseman
A5012837749- Heat shock proteins research
- Molecular Biology Techniques and Applications
- Endoplasmic Reticulum Stress and Disease
- Cancer Research and Treatments
- Asymmetric Synthesis and Catalysis
- Synthetic Organic Chemistry Methods
- Cyclopropane Reaction Mechanisms
- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Chemical Synthesis and Analysis
- ATP Synthase and ATPases Research
- Computational Drug Discovery Methods
- Chemical synthesis and alkaloids
- Oxidative Organic Chemistry Reactions
- Click Chemistry and Applications
- X-ray Diffraction in Crystallography
- Peptidase Inhibition and Analysis
- Crystallization and Solubility Studies
- Pneumocystis jirovecii pneumonia detection and treatment
- thermodynamics and calorimetric analyses
- Carbohydrate Chemistry and Synthesis
- Toxin Mechanisms and Immunotoxins
- Quinazolinone synthesis and applications
- Viral Infectious Diseases and Gene Expression in Insects
- Advanced Synthetic Organic Chemistry
Institute of Cancer Research
2015-2025
CRUK Lung Cancer Centre of Excellence
2022
Cancer Research UK
2015-2021
Institute of Cancer Research
2016
University of Bath
2005-2011
GlaxoSmithKline (United Kingdom)
2009
University of Oxford
2008
Demonstrating intracellular protein target engagement is an essential step in the development and progression of new chemical probes potential small molecule therapeutics. However, this can be particularly challenging for poorly studied noncatalytic proteins, as robust proximal biomarkers are rarely known. To confirm that our recently discovered probe 1 (CCT251236) binds putative transcription factor regulator pirin living cells, we developed a heterobifunctional degradation probe. Focusing...
CCT251236 1, a potent chemical probe, was previously developed from cell-based phenotypic high-throughput screen (HTS) to discover inhibitors of transcription mediated by HSF1, factor that supports malignancy. Owing its activity against models refractory human ovarian cancer, 1 progressed into lead optimization. The reduction P-glycoprotein efflux became focus early compound optimization; central ring halogen substitution demonstrated matched molecular pair analysis be an effective strategy...
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 drug discovery. In this article, we describe the discovery of a new chemical probe, bisamide (CCT251236), identified using unbiased phenotypic screen to detect inhibitors HSF1 stress pathway. The probe is orally bioavailable displays efficacy in human ovarian carcinoma xenograft...
Abstract 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 cells difficult owing to competition the high affinity and abundance of its endogenous nucleotide substrates. We hypothesized could be overcome using a cysteine‐targeted irreversible inhibitor. Using rational design, we adapted validated 8‐ N ‐benzyladenosine ligand for...
The covalent inhibition mechanism of action, which overcomes competition with high-affinity, high-abundance substrates challenging protein targets, can deliver effective chemical probes and drugs. success this strategy has centered on exposed cysteine residues as nucleophiles but the low abundance in proteome limited its application. We have recently reported our discovery that lysine-56 difficult-to-drug target HSP72 could form a bond small-molecule inhibitor. now disclose optimization...
A general strategy for the production of pyrrolizidine alkaloids is described, starting from intermediate (+)−9. The key features are diastereoselective dihydroxylation, inversion at ring junction by hydroboration an enamine, and closure to form bicyclo system. This route attractive because its brevity versatility; four natural products were prepared with differing stereochemistry substitution patterns. Finally, this work allowed assignment absolute 2,3,7-triepiaustraline hyacinthacine A7.
HSP70 is a molecular chaperone and key component of the heat-shock response. Because its proposed importance in oncology, this protein has become popular target for drug discovery, efforts which have as yet brought little success. This study demonstrates that adenosine-derived inhibitors potentially bind to with novel mechanism action, stabilization by desolvation an intramolecular salt-bridge induces conformational change protein, leading high affinity ligands. We also demonstrate through...
Abstract Purpose: Advanced prostate cancer (PCa) is invariably fatal with the androgen receptor (AR) being a major therapeutic target. AR signaling inhibitors have improved overall survival for men advanced PCa, but treatment resistance inevitable and includes reactivation of signaling. Novel approaches targeting these mechanisms to block tumor growth an urgent unmet clinical need. One attractive strategy target heat shock proteins critical functional activity. Experimental Design: We first...
<p>NXP800-resistant 22Rv1 prostate cancer cell sublines demonstrate the reversal of NXP800-mediated phenotype. <b>A,</b> Long-term treatment cells with increasing concentrations (up to 2.5 μmol/L) DMSO (vehicle-C, white), CCT365248 (inactive-C, blue), and NXP800 (NXP800-R, red) led generation cell–derived sublines. Mean growth was determined after 5 days by CellTiter-Glo Luminescent Cell Viability Assay compared day 0 vehicle-C SD for each subline developed is shown....
<p>Supplementary figure 6: Inhibition of the unfolded protein response with ISRIB rescues NXP800-mediated suppression AR signaling and PCa model growth</p>
<p>GO cellular response to heat gene expression signature associates with AR signaling and poorer prognosis in men suffering from CRPC. <b>A</b> <b>G,</b> Two independent (PCF-SU2C ICR-RMH) transcriptome cohorts of patients Quantification GO each cohort CRPC the PCF-SU2C (<b>A</b>) ICR-RMH (<b>G</b>) cohorts. Biopsies (red dots) >80th percentile (dotted line) are shown. <b>B</b> <b>H,</b> Kaplan–Meier curves for...
<p>Supplementary figure 2: AR and AR-V7 bind members of the 70KDa heat shock protein family mediated cellular stress increases HSP72 expression, associates with GO Cellular Response to Heat gene expression signature, in PCa cells</p>
<p>NXP800 inhibits the growth of AR-dependent and AR-independent prostate cancer models with activation UPR inhibition key signaling pathways. <b>A</b> <b>B,</b> PDX-O [CP50, CP89, CP129, CP142 (<b>A</b>)], AR-positive (VCaP, LNCaP, LNCaP95, 22Rv1), AR-negative (PC3 DU145) cell lines (<b>B</b>) were treated vehicle (DMSO 0.1%) or various concentrations (5, 10, 50, 100, 250 nmol/L) NXP800 (active, red line), CCT365248 (inactive, blue in...
<p>Supplementary figure 1: Chemical structures of NXP800 and CCT365248</p>
<p>Supplementary figure 3: GO Cellular Response to Heat gene expression signature associates with AR signaling in CRPC transcriptomes</p>
<p>NXP800 activates the UPR and inhibits key signaling pathways identifying a novel mechanism of action in prostate cancer models. <b>A,</b> VCaP, LNCaP95, 22Rv1 cells were treated with 250 nmol/L CCT365248 (inactive) or NXP800 (active) for 24 hours prior to addition puromycin 30 minutes. PERK, phospho-eIF2α, ATF4 (PERK arm); ATF6 (ATF6 IRE1 (IRE1 arm) protein; E2F1; (incorporation surrogate protein synthesis); GAPDH (housekeeping) expression was determined by Western blot...
<p>Supplementary figure 4: NXP800 decreases basal HSP72 protein levels and blocks induction in response to HSP90 inhibition PCa cell lines</p>
<div>AbstractPurpose:<p>Advanced prostate cancer is invariably fatal, with the androgen receptor (AR) being a major therapeutic target. AR signaling inhibitors have improved overall survival for men advanced cancer, but treatment resistance inevitable and includes reactivation of signaling. Novel approaches targeting these mechanisms to block tumor growth an urgent unmet clinical need. One attractive strategy target heat shock proteins (HSP) critical functional...
<p>Supplementary figure 9: NXP800 demonstrates tolerability in a castration-resistant VCaP PCa cell line-derived mouse xenograft</p>
<p>Supplementary figure 7: NXP800 does not decrease basal HSP72 protein levels and HSP90 inhibitor-induced induction in NXP800-resistant 22Rv1 PCa cell sub-lines</p>
<p>NXP800 inhibits AR transactivation and signaling to inhibit the growth of aberrant prostate cancer models. <b>A–C,</b> VCaP (<b>A</b>), LNCaP95 (<b>B</b>), 22Rv1 (<b>C</b>) cells were treated with vehicle (DMSO 0.1%) or various concentrations (5, 10, 50, 100, 250 nmol/L) NXP800 (active, red line) CCT365248 (inactive, blue line), was determined after 5 days by CellTiter-Glo Luminescent Cell Viability Assay. Mean (compared vehicle;...
<p>Supplementary figure 10: NXP800 demonstrates limited impact on AR and AR-V7 protein levels associated signaling in-vivo but does induce apoptosis reduce cellular proliferation</p>