A5032576859- Lung Cancer Treatments and Mutations
- Cancer therapeutics and mechanisms
- Angiogenesis and VEGF in Cancer
- PI3K/AKT/mTOR signaling in cancer
- HER2/EGFR in Cancer Research
- Tuberculosis Research and Epidemiology
- Cell Adhesion Molecules Research
- Cytokine Signaling Pathways and Interactions
- Monoclonal and Polyclonal Antibodies Research
- Advanced Breast Cancer Therapies
- Prostate Cancer Treatment and Research
- Cancer Mechanisms and Therapy
- Cancer, Lipids, and Metabolism
- Colorectal Cancer Treatments and Studies
- Quinazolinone synthesis and applications
- Chronic Lymphocytic Leukemia Research
- FOXO transcription factor regulation
- Gastric Cancer Management and Outcomes
- Cancer Genomics and Diagnostics
- Chemical Synthesis and Analysis
- Cancer Cells and Metastasis
- Hepatocellular Carcinoma Treatment and Prognosis
- Protein Degradation and Inhibitors
- Developmental Biology and Gene Regulation
- Biotin and Related Studies
AstraZeneca (United Kingdom)
2012-2025
Liechtenstein Institute
2023
Hudson Institute
2023
John Wiley & Sons (United States)
2023
AstraZeneca (Brazil)
2013
First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm(+)) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M TKI resistance mutation. AZD9291 is novel oral, potent, and selective third-generation irreversible inhibitor both EGFRm(+) sensitizing mutants that spares wild-type EGFR. This mono-anilino-pyrimidine compound...
A novel series of small-molecule inhibitors has been developed to target the double mutant form epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this was evolved a cysteine residue in ATP binding site via covalent bond formation demonstrates high levels activity cellular models In addition, these significant against activating...
Abstract Off‐target pharmacology may contribute to both adverse and beneficial effects of a new drug. In vitro pharmacological profiling is often applied early in drug discovery; there are fewer reports addressing the relevance broad profiles clinical effects. Here, we have characterized profile active metabolite fostamatinib, R406, linking an understanding selectivity increase blood pressure observed studies. R406 was profiled range assays generate comprehensive key targets were further...
Abstract Background/objective To explore the anti-tumour activity of combining AKT inhibition and docetaxel in PTEN protein null WT prostate tumours. Methods Mechanisms associated with capivasertib treatment cancer were examined using a panel vivo tumour models cell lines. Results Combining had increased vivo. In vitro short-term caused cycle arrest majority cells. However, sub-population docetaxel-persister cells did not undergo G2/M but upregulated phosphorylation PI3K/AKT pathway...
The Notch signaling pathway has been implicated in cell fate determination and differentiation many tissues. Accumulating evidence points toward a pivotal role blood vessel formation, the importance of Delta-like ligand (Dll) 4-Notch1 ligand-receptor interaction shown both physiological tumor angiogenesis. Disruption this leads to reduction growth as result an increase nonfunctional vasculature leading poor perfusion tumor. MEDI0639 is investigational human therapeutic antibody that targets...
Abstract The PI3K pathway is commonly activated in breast cancer, with PI3K-AKT inhibitors used clinically. However, mechanisms that limit or enhance the therapeutic effects of are poorly understood at a genome-wide level. Parallel CRISPR screens 3 PTEN-null cancer cell lines identified genes mediating resistance to capivasertib (AKT inhibitor) and AZD8186 (PI3Kβ inhibitor). dominant mechanism causing reactivated PI3K-AKT-mTOR signalling, but not other canonical signalling pathways. Deletion...
Combining the selective AKT inhibitor, capivasertib, and SERD, fulvestrant improved PFS in a Phase III clinical trial (CAPItello-291), treating HR+ breast cancer patients following aromatase inhibitors, with or without CDK4/6 inhibitors. However, data suggests treatment may reduce response to subsequent monotherapy endocrine treatment. To support understanding of trials such as CAPItello-291 gain insight into this emerging population patients, we explored how inhibitor influences ER+ tumour...
Metabolic plasticity is an emerging hallmark of cancer, and increased glycolysis often observed in transformed cells. Small molecule inhibitors that target driver oncogenes can potentially inhibit the glycolytic pathway. Osimertinib (AZD9291) a novel EGFR tyrosine kinase inhibitor (TKI) potent selective for sensitising (EGFRm) T790M resistance mutations. Clinical studies have shown osimertinib to be efficacious patients with EGFRm/ advanced NSCLC who progressed after EGFR-TKI treatment....
Capivasertib is a potent, selective inhibitor of all 3 Akt isoforms (Akt1/2/3), and it currently being tested in Phase III trials for the treatment prostate breast cancer. To investigate effect cytochrome P450 3A4 (CYP3A4) on pharmacokinetics capivasertib, I drug-drug interaction study capivasertib itraconazole was conducted 11 healthy volunteers (median age, 54 years). The 8-day had stages: Participants received single dose 80 mg Stage 1, 4 doses 200 over days 2, final coadministered with...
Abstract Inhibition of the androgen receptor (AR) is primary treatment for metastatic hormone-sensitive prostate cancer (mHSPC). The addition antiandrogen therapies to deprivation therapy (ADT) has greatly improved patient outcomes. However, loss tumor suppressor PTEN common in (PCa), and resulting increase AKT signaling contributes PCa progression. Capivasertib (AZD5363) currently being investigated as an oral pan-AKT inhibitor combination with abiraterone (Abi) ADT treating mHSPC patients...
Abstract Taxane chemotherapy is the standard treatment for metastatic castration-resistant prostate cancer (mCRPC). The tumor suppressor PTEN frequently deleted in advanced (PCa), contributing to progression and poor clinical outcomes. Hyperactivation of AKT resulting from loss reciprocal crosstalk between AR PI3K/AKT signaling may impair efficacy taxane therapy. Capivasertib (AZD5363) a potent oral pan-AKT inhibitor that has shown against PCa preclinical early phase studies. currently being...
Abstract Breast cancer is one of the most common cancers worldwide, and around 80% breast are oestrogen receptor positive (ER+ BC). For patients with ER+ advanced BC or more PIK3CA/AKT1/PTEN tumor alterations, capivasertib (AKT inhibitor) in combination fulvestrant (selective (ER) degrader) a recommended treatment. An innate PI3K/AKT pathway inhibitor resistance can occur BC, limiting their efficacy. Therefore, novel therapeutic strategies needed to increase sensitivity treatments BC. With...
Abstract Combining fulvestrant (a selective estrogen receptor (ER) degrader) with the PI3K-AKT signalling inhibitors such as alpelisib (PI3Kα inhibitor) or capivasertib (AKT gives benefit to patients ER+ breast cancer (ER+ BC) harboring PIK3CA mutations (alpelisib) and PIK3CA, PTEN AKT-1 altered tumors (capivasertib). While are common, activation can also occur due other alterations, including in AKT-1, which alter pathway function dependency. Deletion of PTEN, leading ablation protein,...
Abstract Loss of PTEN expression, via homozygous or hemizygous deletion, is common in PIK3CA mutant ER + BC tumors. We assessed reduction protein expression on AKT inhibitor capivasertib efficacy altered In altered, high models, PI3Kα and inhibition was effective, however ablation partial attenuated PI3Kαi but not AKTi efficacy, alone combined with fulvestrant. Efficacy FOXO3 dependent associated FOXM1 downregulation. FOXO3A deletion reduced response to capivasertib, increased expression....
Inhibition of VEGFR-2 signaling reduces angiogenesis and retards tumor growth. Current biotherapeutics that inhibit by either sequestering VEGF ligand or inhibiting binding to may be compromised high concentrations. Here we describe a biotherapeutic targets Ig domains 4-7 therefore has the potential work independently concentration. 33C3, fully human antibody, was generated using XenoMouse technology. To elucidate mechanism action have used number competition assays. We show 33C3 binds 4-7,...
Abstract The first generation EGFR TKIs gefitinib and erlotinib provide significant clinical benefit in patients with advanced lung adenocarcinoma harbouring activating mutants (EGFRm+), but will ultimately develop disease progression due to acquired resistance. Acquisition of the T790M mutation is most common mechanism drug resistance, detected more than 50% gefitinib/erlotinib resistant patients. Current therapeutic strategies are limited for (EGFRm+/T790M), so this remains a key area...
Overactivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives this analysis were to develop population pharmacokinetic model for capivasertib and quantitatively assess impact intrinsic extrinsic factors on pharmacokinetics capivasertib.
A novel series of covalent inhibitors EGFR (epidermal growth factor receptor) kinase was discovered through a combination subset screening and structure-based design. These compounds preferentially inhibit mutant forms (activating T790M mutant) over wild-type in cellular assays measuring autophosphorylation proliferation, suggesting an improved therapeutic index non-small cell lung cancer patients would be achievable relative to established inhibitors. We describe our design approaches,...
Abstract Aberrant receptor tyrosine kinase (RTK) signaling is a well-documented driver of disease onset and progression across myriad cancer types, where the MET RTK contributes to tumor progression, maintenance resistance targeted therapies. Here we explore therapeutic potential AZD6094, highly potent selective inhibitor, in EGFR mutant (EGFRm) non-small cell lung (NSCLC). Although many EGFRm NSCLC patients receiving first-line Tyrosine Kinase Inhibitors (TKI) benefit from therapy...