A5014622191- PI3K/AKT/mTOR signaling in cancer
- Advanced Breast Cancer Therapies
- Cancer Genomics and Diagnostics
- Lung Cancer Treatments and Mutations
- Cancer Diagnosis and Treatment
- Cancer Treatment and Pharmacology
- Cancer, Lipids, and Metabolism
- Cancer-related Molecular Pathways
- Prostate Cancer Treatment and Research
- Cancer-related molecular mechanisms research
- CRISPR and Genetic Engineering
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Cancer therapeutics and mechanisms
- Autophagy in Disease and Therapy
- RNA modifications and cancer
- Synthesis and Reactivity of Heterocycles
- Cancer Mechanisms and Therapy
- Chronic Lymphocytic Leukemia Research
- Microtubule and mitosis dynamics
- HER2/EGFR in Cancer Research
- Protein Kinase Regulation and GTPase Signaling
- Enzyme function and inhibition
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Bioactive Compounds and Antitumor Agents
- Cancer Immunotherapy and Biomarkers
AstraZeneca (United Kingdom)
2003-2023
Novartis (Switzerland)
2013
AstraZeneca (Switzerland)
2013
The University of Texas MD Anderson Cancer Center
2013
Levine Cancer Institute
2013
Novartis Institutes for BioMedical Research
2013
Carolinas Healthcare System
2013
GW Pharmaceuticals (United Kingdom)
2009
The Aurora/Ipl1 family of protein kinases plays multiple roles in mitosis and cytokinesis. Here, we describe ZM447439, a novel selective Aurora kinase inhibitor. Cells treated with ZM447439 progress through interphase, enter normally, assemble bipolar spindles. However, chromosome alignment, segregation, cytokinesis all fail. Despite the presence maloriented chromosomes, ZM447439-treated cells exit normal kinetics, indicating that spindle checkpoint is compromised. Indeed, prevents mitotic...
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...
A nanoparticle formulation of an Aurora B kinase inhibitor uses ion pairing to achieve controlled release and efficacious, nontoxic target inhibition in tumors.
Activating mutations in KRAS underlie the pathogenesis of up to 20% human tumors, and is one most frequently mutated genes cancer. Developing therapeutics block activity has proven difficult, no direct inhibitor function entered clinical trials. We describe preclinical evaluation AZD4785, a high-affinity constrained ethyl-containing therapeutic antisense oligonucleotide (ASO) targeting mRNA. AZD4785 potently selectively depleted cellular mRNA protein, resulting inhibition downstream effector...
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...
The PIK3CA gene, encoding the p110α catalytic unit of PI3Kα, is one most frequently mutated oncogenes in human cancer. Hence, PI3Kα a target subject to intensive efforts identifying inhibitors and evaluating their therapeutic potential. Here, we report studies with novel PI3K inhibitor, AZD8835, currently phase I clinical evaluation. AZD8835 potent inhibitor PI3Kδ selectivity versus PI3Kβ, PI3Kγ, other kinases that preferentially inhibited growth cells mutant status, such as estrogen...
Purpose: PTEN-null tumors become dependent on the PI3Kβ isoform and can be targeted by molecules such as selective inhibitor AZD8186. However, beyond modulation of canonical PI3K pathway, consequences inhibiting are poorly defined.Experimental Design: To determine broader impact AZD8186 in tumors, we performed a genome-wide RNA-seq analysis triple-negative breast tumor xenografts treated with Mechanistic treatment were examined across number cell lines models.Results: resulted modification...
Abstract Purpose: The phosphoinositide 3-kinase (PI3K) pathway is a major oncogenic signaling and an attractive target for therapeutic intervention. Signaling through the PI3K moderated by tumor suppressor PTEN, which deficient or mutated in many human cancers. Molecular characterization of network has not been well defined lung cancer; particular, role PI3Kβ its relation to PTEN non–small cell cancer NSCLC remain unclear. Experimental Design: Antibodies directed against were validated used...
Abstract AZD8186 is a novel potent small molecule that targets the lipid kinase PI3Kβ with selectivity vs PI3Kα. reduces pAKT-S473 in PTEN deficient MDA-MB-468 cell line an IC50 <5nM, while PI3Kα-dependent PIK3CA mutant BT474 it 200 fold less potent. also demonstrates cellular activity versus PI3Kβ, inhibiting IgM-dependent of 15nM. In panels, sensitivity to associated part loss function suggesting targeting tumours have lost normal levels through deletion, mutation or down regulation...
Abstract The prodrug, Barasertib (AZD1152) is a potent selective inhibitor of the Aurora B kinase which plays pivotal role in chromosomal segregation during cell cycle. In Phase 2 randomised study elderly AML patients unfit for intensive therapy, showed statistically significant improvement Overall Complete Response Rate and trend improved Survival as continuous infusion over 7 days (Kantarjian et al, Cancer 2013;119:2611-2619) . Dose Limiting Toxicities were neutropenia stomatitis....
Abstract The PIK3CA gene, encoding the p110 catalytic unit of PI3Kα, is one most frequently mutated oncogenes described in human cancer. Hence PI3Kα a target subject to intensive efforts identifying inhibitors and evaluating their therapeutic potential. To date studies with PI3K have used continuous (daily) dosing schedule although clinical responses been reported overall activity observed has moderate. This may part be due suboptimal pathway inhibition which capped by normal tissue...
Abstract AZD8186 inhibits Pi3K isoforms Pi3Kβ and δ, with selectivity over Pi3Kα γ. In solid tumours drives tumour growth when the suppressor PTEN is deleted, mutated or downregulated. It also mediates signals from specific GPCR receptors. Pi3Kδ downstream of B-cell receptor, creating potential for targeted treatment haematological malignancies such as CLL, MCL & indolent NHL possibly DLBCL. differentiated many other agents that target family members it isn't likely to impact glucose...
Abstract KRAS is one of the most frequently mutated genes in cancer and its activation thought to underlie pathogenesis up 30% all human tumors. However, date has proven difficult target with traditional pharmacologic approaches. Antisense technology particularly attractive for such drug targets as antisense oligonucleotide (ASO) inhibitors can be designed based on a RNA sequence alone. cEt ASOs have been recently described demonstrated significantly increased potency over previous...
Abstract AZD8186 inhibits the PI3K isoforms PI3Kβ and δ In solid tumors when tumor suppressor PTEN is deleted, mutated or downregulated becomes a key driver of cell growths. hematological such as DLBCL down-regulated, moreover PI3Kδ important in signaling from B-cell receptor, creating potential for targeted treatment malignancies. has single agent activity range pre-clinical models representative different types. However efficacy agents pathway are anticipated to be limited by compensatory...
Abstract Urothelial Cell Carcinoma (UCC) is the fifth most common cancer, but no new generation molecularly targeted therapies have been registered to treat this disease. Non muscle-invasive bladder cancer can be treated by systemic or intravesical dosing routes. However, urothelium one of formidable permeability barriers in nature, and may limit penetration small molecules into tumour tissue from location. Inhibitors mitosis, including spindle proteins such as Eg5, are attractive targets...