A5058325442- Computational Drug Discovery Methods
- PI3K/AKT/mTOR signaling in cancer
- Prostate Cancer Treatment and Research
- Cancer, Lipids, and Metabolism
- Biosimilars and Bioanalytical Methods
- Health Systems, Economic Evaluations, Quality of Life
- Protein Degradation and Inhibitors
- Autophagy in Disease and Therapy
- Advanced Breast Cancer Therapies
- Cancer-related Molecular Pathways
- Biochemical and Molecular Research
- Microtubule and mitosis dynamics
- Ubiquitin and proteasome pathways
- Chronic Lymphocytic Leukemia Research
- Protein Kinase Regulation and GTPase Signaling
- Chemical Reactions and Isotopes
- Cancer, Hypoxia, and Metabolism
- Amino Acid Enzymes and Metabolism
- Pharmacogenetics and Drug Metabolism
- Synthesis and Catalytic Reactions
- Acute Myeloid Leukemia Research
- Histone Deacetylase Inhibitors Research
- Click Chemistry and Applications
- Hormonal and reproductive studies
- Cancer Mechanisms and Therapy
AstraZeneca (United Kingdom)
2013-2024
Bioscience Research
2019
AstraZeneca (Canada)
2012-2018
University of Bradford
2018
The Prostate Centre
2012-2013
University of British Columbia
2012-2013
Cancer Research UK
2007
AKT is a key node in the most frequently deregulated signaling network human cancer. AZD5363, novel pyrrolopyrimidine-derived compound, inhibited all isoforms with potency of 10 nmol/L or less and phosphorylation substrates cells approximately 0.3 to 0.8 μmol/L. AZD5363 monotherapy proliferation 41 182 solid hematologic tumor cell lines 3 μmol/L less. Cell derived from breast cancers showed highest frequency sensitivity. There was significant relationship between presence PIK3CA and/or PTEN...
Abstract Purpose: In the current study, we examined in vivo effects of AZD1152, a novel and specific inhibitor Aurora kinase activity (with selectivity for B). Experimental Design: The pharmacodynamic efficacy AZD1152 were determined panel human tumor xenograft models. was dosed via several parenteral (s.c. osmotic mini-pump, i.p., i.v.) routes. Results: potently inhibited growth colon, lung, hematologic xenografts (mean inhibition range, 55% to ≥100%; P < 0.05) immunodeficient mice....
The Aurora kinases, a family of mitotic regulators, have received much attention as potential targets for novel anti-cancer therapeutics. Several kinase inhibitors been described including ZM447439, which prevents chromosome alignment, spindle checkpoint function and cytokinesis. Subsequently, ZM447439-treated cells exit mitosis without dividing lose viability. Because ZM447439 inhibits both A B, we set out to determine phenotypes are due inhibition kinase. Using molecular genetic...
The Aurora kinases have been the subject of considerable interest as targets for development new anticancer agents. While evidence suggests inhibition B kinase gives rise to more pronounced antiproliferative phenotype, most clinically advanced agents reported date typically inhibit both A and B. We discovered a series pyrazoloquinazolines, some which show greater than 1000-fold selectivity over activity, in recombinant enzyme assays. These compounds designed parenteral administration achieve...
Wide-ranging exploration of analogues an ATP-competitive pyrrolopyrimidine inhibitor Akt led to the discovery clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism pharmacokinetics (DMPK) properties and, after oral dosing, pharmacodynamic knockdown phosphorylation downstream biomarkers in vivo, inhibition tumor growth a breast cancer xenograft model.
The cyclin dependent kinase (CDK)-retinoblastoma (RB)-E2F pathway plays a critical role in the control of cell cycle estrogen receptor-positive (ER
The progression to castration-resistant prostate cancer (CRPC) correlates with gain-of-function of the androgen receptor (AR) and activation AKT. However, as single agents, AR or AKT inhibitors result in a reciprocal feedback loop. Therefore, we hypothesized that combination an inhibitor antiandrogen might more profound, long-lasting remission CRPC. Here, report AZD5363 potently inhibits proliferation induces apoptosis cell lines expressing has anticancer activity vivo androgen-sensitive...
SGK3 is a PX domain containing protein kinase activated at endosomes downstream of class 1 and 3 PI3K family members by growth factors oncogenic mutations. plays key role in mediating resistance breast cancer cells to or Akt inhibitors, substituting for the loss activity restoring proliferative pathways such as mTORC1 signaling. It therefore critical develop tools potently target obstruct its inhibitor resistance. Here, we describe development SGK3-PROTAC1, PROTAC conjugate 308-R SGK with...
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...
Abstract Targeting the estrogen receptor alpha (ERα) pathway is validated in clinic as an effective means to treat ER+ breast cancers. Here we present development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation ER antagonism cancer cell lines. However, upon dosing compound vivo observe - disconnect. lower than expected based on data. Investigation into potential causes for...
Abstract Purpose: Prostate cancer development is often associated with deletion or silencing of tumor suppressor phosphatase and tensin homolog (PTEN), a negative regulator the phosphoinositide 3 kinase (PI3K)–Akt pathway, leading to resistance various therapies in both preclinical clinical setting. Therefore, PI3K–Akt pathway plays central role cellular processes promoting survival signaling that can contribute malignant phenotype, and, consequently, an attractive pharmacologic target....
Article1 August 2016Open Access Source DataTransparent process The hVps34-SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumour growth Ruzica Bago Corresponding Author MRC Protein Phosphorylation Ubiquitylation Unit, College of Life Sciences, University Dundee, UK Search for more papers this author Eeva Sommer Pau Castel Human Oncology Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA Claire Crafter iMED, AstraZeneca, CRUK...
PI3K inhibitors with differential selectivity to distinct isoforms have been tested extensively in clinical trials, largely target tumor epithelial cells. signaling also regulates the immune system and inhibition of PI3Kδ modulate microenvironment pre-clinical mouse models by relieving T-regs-mediated immunosuppression. as a class specifically are associated immune-related side effects. However, impact mixed immunology is under-explored. Here we examine effects AZD8835, dual PI3Kα/δ...
Abstract Loss of PTEN protein results in upregulation the PI3K/AKT pathway, which appears dependent on PI3Kβ isoform. Inhibitors have potential to reduce growth tumors loss drives tumor progression. We developed a small-molecule inhibitor and PI3Kδ (AZD8186) assessed its antitumor activity across panel cell lines. then explored effects as single agent combination with docetaxel triple-negative breast (TNBC) prostate cancer models. In vitro, AZD8186 inhibited range Sensitivity was associated...
More than 50% of human tumors display hyperactivation the serine/threonine kinase AKT. Despite evidence clinical efficacy, therapeutic window current generation AKT inhibitors could be improved. Here, we report development a second-generation degrader, INY-05-040, which outperformed catalytic inhibition with respect to cellular suppression AKT-dependent phenotypes in breast cancer cell lines. A growth screen 288 lines confirmed that INY-05-040 had substantially higher potency our...
Aurora kinases play a critical role in regulating mitosis and cell division, their overexpression has been implicated the survival proliferation of human cancer. In this study, we report vitro vivo activities AZD1152, compound that selectivity for aurora B kinase, acute myeloid leukemia (AML) lines, primary AML samples, cord blood cells. AZD1152 exerted antiproliferative or cytotoxic effects all lines studied, inhibited phosphorylation histone H3 (pHis H3) on Ser10 dose-dependent manner,...
Abstract AKT1E17K mutations occur at low frequency in a variety of solid tumors, including those the breast and urinary bladder. Although this mutation has been shown to transform rodent cells culture, it was found be less oncogenic than PIK3CA epithelial cells. Moreover, therapeutic potential AKT inhibitors human tumors with an endogenous is not known. Expression exogenous copies MCF10A increased phosphorylation its substrates, induced colony formation soft agar, lesions mammary fat pad...
We report the first disclosure of IRAK3 degraders in scientific literature. Taking advantage an opportune byproduct obtained during our efforts to identify IRAK4 inhibitors, we identified ready-to-use, selective ligands compound collection with required properties for conversion into proteolysis-targeting chimera (PROTAC) degraders. This work culminated discovery PROTAC 23, which demonstrated be a potent and degrader after 16 h THP1 cells. 23 induced proteasome-dependent degradation both...
Wide-ranging exploration of potential replacements for a quinoline-based inhibitor activation AKT kinase led to number alternative, novel scaffolds with potentially improved potency and physicochemical properties. Examples showed predictable DMPK properties, one such compound demonstrated pharmacodynamic knockdown phosphorylation downstream biomarkers in vivo inhibition tumor growth breast cancer xenograft model.
Abstract Objectives: The androgen receptor (AR) is highly expressed in prostate cancers and a clinically validated target oncology. AZD9750 novel potent oral selective AR Proteolysis-targeting chimera (PROTAC) due to start clinical testing 2025. We present here the preclinical PK/PD modeling work used understand required modulation concentration see anti-tumor efficacy therefore help support dose selection during early development of AZD9750. Methods: developed mechanistic mathematical model...
The androgen receptor (AR) is a member of the nuclear hormone superfamily and key driver prostate tumor growth. Several pathway inhibitors (ARPIs) have been developed approved for treatment locally advanced metastatic cancer, including synthesis inhibitor, abiraterone AR antagonists, enzalutamide, apalutamide darolutamide. Despite initial success resistance does occur, often involving alterations in itself, such as amplification or point mutations ligand binding domain (LBD). Therefore,...
The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling network is frequently de-regulated in breast cancer and has been shown to mediate resistance anti-HER2 agents. Whilst constitutive activation this pathway emerging as a marker sensitivity various PI3K inhibitors, activity these agents the clinic may be limited by presence feedback loops, leading reactivation receptor tyrosine kinases, such HER2/HER3. To determine whether inhibition HER2 could...
// James T. Lynch 1 , Robert McEwen Claire Crafter Ultan McDermott 2 Mathew J. Garnett Simon Barry R. Davies Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, United Kingdom Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, Correspondence to: Lynch, e-mail: james.t.lynch@astrazeneca.com Keywords: PI3K, AKT, mTOR, Notch, leukemia Received: November 16, 2015 Accepted: February 18, 2016 Published: March 10, ABSTRACT Selective phosphoinositide...