A5057710096- Cancer, Hypoxia, and Metabolism
- Computational Drug Discovery Methods
- PARP inhibition in cancer therapy
- Estrogen and related hormone effects
- PI3K/AKT/mTOR signaling in cancer
- Metabolomics and Mass Spectrometry Studies
- Advanced Breast Cancer Therapies
- Biosimilars and Bioanalytical Methods
- Cancer, Lipids, and Metabolism
- Phytochemicals and Medicinal Plants
- Toxin Mechanisms and Immunotoxins
- CRISPR and Genetic Engineering
- Health Systems, Economic Evaluations, Quality of Life
- DNA Repair Mechanisms
- RNA modifications and cancer
- Metabolism, Diabetes, and Cancer
- Lanthanide and Transition Metal Complexes
- Receptor Mechanisms and Signaling
- Metabolism and Genetic Disorders
- Prostate Cancer Treatment and Research
- Cancer therapeutics and mechanisms
- Mitochondrial Function and Pathology
- Diabetes Treatment and Management
- Epigenetics and DNA Methylation
- ATP Synthase and ATPases Research
AstraZeneca (United Kingdom)
2015-2025
AstraZeneca (Brazil)
2021
Saffron Walden Museum
2018
University of Birmingham
2015
Laboratoire de Génie des Procédés Catalytiques
2015
Manchester Academic Health Science Centre
2013
University of Manchester
2013
Newcastle University
2013
Health Sciences Centre
2013
National Health Service
2013
The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, survival, autophagy. Allosteric inhibitors mTORC1, such as rapamycin, have been extensively used to study tumor proliferation, autophagy but shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor mTOR activity, with an IC50 0.8 nmol/L. AZD8055 showed excellent selectivity (approximately 1,000-fold) against all class I...
Highlights•ACSS2 expression positively correlates with tumor stage and patient survival•Hypoxia low lipid availability synergistically stimulate ACSS2 expression•Acetate is a major source of carbon for synthesis during metabolic stress•ACSS2 required growth xenografts harboring copy-number gainsSummaryA functional genomics study revealed that the activity acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell under low-oxygen lipid-depleted conditions. Comparative metabolomics lipidomics...
Malignant tumors exhibit increased dependence on glycolysis, resulting in abundant export of lactic acid, a hypothesized key step tumorigenesis. Lactic acid is mainly transported by two H(+)/lactate symporters, MCT1/MCT4, that require the ancillary protein CD147/Basigin for their functionality. First, we showed blocking MCT1/2 Ras-transformed fibroblasts with AR-C155858 suppressed lactate export, and tumor growth, whereas ectopic expression MCT4 these cells conferred resistance to inhibition...
Abstract Purpose: The monocarboxylate transporter 1 (MCT1) inhibitor, AZD3965, is undergoing phase I evaluation in the United Kingdom. AZD3965 proposed, via lactate transport modulation, to kill tumor cells reliant on glycolysis. We investigated therapeutic potential of small cell lung cancer (SCLC) seeking rationale for clinical testing this disease and putative predictive biomarkers trial use. Experimental Design: sensitivity was determined seven SCLC lines, normoxia hypoxia, a xenograft...
Enhanced macromolecule biosynthesis is integral to growth and proliferation of cancer cells. Lipid has been predicted be an essential process in However, it unclear which enzymes within this pathway offer the best selectivity for cells could suitable therapeutic targets. Using functional genomics, we identified stearoyl-CoA desaturase (SCD), enzyme that controls synthesis unsaturated fatty acids, as breast prostate SCD inhibition altered cellular lipid composition impeded cell viability...
Monocarboxylate transporter 1 (MCT1) inhibition is thought to block tumor growth through disruption of lactate transport and glycolysis. Here, we show MCT1 impairs proliferation glycolytic breast cancer cells co-expressing MCT4 via pyruvate rather than export. expression elevated in tumors, high predicts poor prognosis lung patients. Acute reduces export but does not consistently alter or flux that co-express MCT4. Despite the lack glycolysis impairment, loss-of-function decreases cell...
Abstract Purpose: We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed selectivity over PARP2, which has been shown play a role in the survival hematopoietic/stem progenitor cells animal models. developed AZD5305 with aim achieving improved clinical efficacy wider therapeutic window. This next-generation PARP inhibitor (PARPi) could provide paradigm shift outcomes achieved by first-generation PARPi,...
Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified potential therapeutic target in area cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography develop small molecule LDHA inhibitors. Fragment hits were through NMR and SPR screening optimized into compounds with nanomolar binding affinities via fragment linking. Also reported is...
Inhibition of the monocarboxylate transporter MCT1 by AZD3965 results in an increase glycolysis human tumor cell lines and xenografts. This is indicated changes levels specific glycolytic metabolites enzyme kinetics. These drug-induced metabolic translate into inhibition growth vivo. Thus, we combined with fractionated radiation to treat small lung cancer (SCLC) xenografts showed that combination provided a significantly greater therapeutic effect than use either modality alone. strongly...
// Nicola J. Curtis 1 , Lorraine Mooney Lorna Hopcroft 2 Filippos Michopoulos Nichola Whalley Haihong Zhong 3 Clare Murray 4,6 Armelle Logie Mitchell Revill Kate F. Byth 5 Amanda D. Benjamin 4 Mike A. Firth Stephen Green Paul Smith and Susan E. Critchlow iMED Oncology, AstraZeneca, Alderley Park, Cheshire, UK Cambridge, MedImmune, One MedImmune Way, Gaithersburg, MD, USA DSM, Gatehouse Waltham, Massachusetts, MA, 6 C4X Discovery, Manchester, Correspondence to: Critchlow, email: Keywords :...
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...
Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some failed combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP lack selectivity PARP1 over PARP2 and other 16 family members, we hypothesized that this could contribute toxicity. Recent literature has demonstrated inhibition PARP1–DNA trapping are...
Abstract Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for receptor–positive (ER+) breast cancer, as they achieve greater inhibition ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated preclinical pharmacology efficacy next-generation oral SERD camizestrant (AZD9833) assessed ER–co-targeting strategies by combining with CDK4/6 inhibitors (CDK4/6i) PI3K/AKT/mTOR-targeted in models...
Abstract Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible is vast be context-specific. Systematic screens identify clinically relevant, actionable in defined patient subtypes. We present data 109 anticancer from AstraZeneca's oncology small molecule portfolio screened 755 pan-cancer cell lines. Combinations were a 7 × concentration matrix, with more than 4 million measurements sensitivity, producing an...
A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. selected example exposure animals following oral dosing. Examples from this series may serve as useful probes to understand emerging biology metabolic target.
Abstract Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical ablation therapies have failed, therefore remains target for the treatment of progressive disease. Here, we describe biological characterization AZD3514, an orally bioavailable drug that inhibits androgen-dependent -independent AR signaling. AZD3514 modulates through two distinct mechanisms, inhibition ligand-driven nuclear translocation...
Described is a quantitative-mass-spectrometry-imaging (qMSI) methodology for the analysis of lactate and glutamate distributions in order to delineate heterogeneity among mouse tumor models used support drug-discovery efficacy testing. We evaluate report on preanalysis-stabilization methods aimed at improving reproducibility efficiency quantitative assessments endogenous molecules tissues. Stability experiments demonstrate that optimum stabilization protocols consist frozen-tissue embedding,...