A5029387768- Cancer, Hypoxia, and Metabolism
- Click Chemistry and Applications
- Computational Drug Discovery Methods
- Melanoma and MAPK Pathways
- HER2/EGFR in Cancer Research
- Lymphoma Diagnosis and Treatment
- Cancer-related Molecular Pathways
- Cytokine Signaling Pathways and Interactions
- Chemical Synthesis and Analysis
- Acute Myeloid Leukemia Research
- Monoclonal and Polyclonal Antibodies Research
- RNA modifications and cancer
- Pharmacological Effects of Natural Compounds
- Peroxisome Proliferator-Activated Receptors
- Advanced biosensing and bioanalysis techniques
- Synthesis and biological activity
- Cancer Mechanisms and Therapy
- Cancer therapeutics and mechanisms
- Metabolism, Diabetes, and Cancer
- Protein Kinase Regulation and GTPase Signaling
Newcastle University
2016-2025
Cancer Research UK
2022
Pfizer (United Kingdom)
2011
Inhibition of monocarboxylate transporter 1 has been proposed as a therapeutic approach to perturb lactate shuttling in tumor cells that lack 4. We examined the inhibitor AZD3965, currently phase I clinical studies, potential therapy for diffuse large B-cell lymphoma and Burkitt lymphoma. Whilst extensive protein was found 120 10 patients' tumors, 4 expression undetectable 73% samples or negligible each sample. AZD3965 treatment led rapid accumulation intracellular panel cell lines with low...
Abstract Background We evaluated the therapeutic potential of combining monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 with mitochondrial respiratory Complex I IACS-010759, for treatment diffuse large B-cell lymphoma (DLBCL), a clinically actionable strategy to target tumour metabolism. Methods and IACS-010759 sensitivity were determined in DLBCL cell lines xenograft models. Lactate concentrations, oxygen consumption rate metabolomics examined as mechanistic endpoints. In vivo plasma...
Abstract The discovery of targeted covalent inhibitors is increasing importance in drug discovery. Finding efficient binders requires modulation warhead reactivity and optimisation geometry non-covalent interactions. Uncoupling the contributions that these factors make to potency difficult best practice for a testing cascade pragmatic informative yet be fully established. We studied structure-reactivity-activity relationships series analogues EGFR inhibitor poziotinib with point changes two...
A major drawback of cytotoxic chemotherapy is the lack selectivity toward noncancerous cells. The targeted delivery drugs to tumor cells a longstanding goal in cancer research. We proposed that covalent inhibitors could be adapted deliver agents, conjugated β-position Michael acceptor, via an addition-elimination mechanism promoted by binding. Studies on model systems showed 5-fluorouracil (5FU) released upon thiol addition relevant time scales. series epidermal growth factor receptor (EGFR)...
The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective inhibitors challenging. Previously, we described a pyrrole carboxamide high-throughput screening hit into selective, submicromolar inhibitor activity. Improvement potency was necessary...
MDM2 is a key negative regulator of the p53 tumor suppressor. Direct binding to represses protein's transcriptional activity and induces its polyubiquitination, targeting it for degradation by proteasome. Consequently, small molecule inhibitors that antagonize MDM2-p53 binding, such as RG7388, have progressed into clinical development aiming reactivate function in TP53 wild-type tumors. Here, we describe design, synthesis, biological evaluation trans-cyclooctene tagged derivative RG7388-TCO,...
Abstract Many tumors display an altered metabolic phenotype with increased reliance on glycolysis resulting in a greater production of the waste product, lactate [1]. Use glycolysis, as opposed to oxidative phosphorylation, represents less efficient means ATP generation but provides selective advantage cancer cells that it rapidly supplies intermediates support anabolic pathways necessary for cellular proliferation. Lactate efflux, is facilitated by monocarboxylate transporters 1-4 and...
<h3>Objective</h3> The activation of p38 MAPK is involved in the increased expression pro-inflammatory cytokines, such as TNF-α and IL-6, inflammatory diseases chronic obstructive pulmonary disease (COPD). Inhibition may therefore represent an effective means to combat diseases. Inhibitors BIRB796 cause a rapid reduction levels cytokines. aim was assess effect three inhibitors on lipopolysaccharide (LPS) induced cytokines; IL-6 IL-10 MDMs. <h3>Methods</h3> Peripheral blood mononuclear cells...