A5059691963- Lung Cancer Treatments and Mutations
- Estrogen and related hormone effects
- Advanced Breast Cancer Therapies
- PI3K/AKT/mTOR signaling in cancer
- HER2/EGFR in Cancer Research
- Chronic Lymphocytic Leukemia Research
- Cancer Treatment and Pharmacology
- Cancer therapeutics and mechanisms
- Fibroblast Growth Factor Research
- Breast Cancer Treatment Studies
- Cancer Cells and Metastasis
- Protein Tyrosine Phosphatases
- Monoclonal and Polyclonal Antibodies Research
- Cytokine Signaling Pathways and Interactions
- Immune cells in cancer
- Cancer Immunotherapy and Biomarkers
- Quinazolinone synthesis and applications
- Tuberculosis Research and Epidemiology
- Cancer Genomics and Diagnostics
- Colorectal Cancer Treatments and Studies
- Cancer, Hypoxia, and Metabolism
- Radiopharmaceutical Chemistry and Applications
- Computational Drug Discovery Methods
- Lung Cancer Research Studies
- PARP inhibition in cancer therapy
AstraZeneca (United Kingdom)
2016-2025
AstraZeneca (United States)
2017-2020
Tennessee Oncology
2017
Memorial Sloan Kettering Cancer Center
2017
The Christie NHS Foundation Trust
2017
Sarah Cannon
2017
Seoul National University Hospital
2017
Sarah Cannon Research Institute
2017
Cancer Research UK Cambridge Center
2017
AstraZeneca (Brazil)
2013-2015
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...
Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number years. Despite encouraging clinical efficacy with these agents, many resistance develops leading to disease progression. In most cases, this is form T790M mutation. addition, EGFR wild type inhibition inherent agents can lead dose limiting toxicities rash and diarrhea. We describe herein...
The fibroblast growth factor (FGF) signaling axis is increasingly implicated in tumorigenesis and chemoresistance. Several small-molecule FGF receptor (FGFR) kinase inhibitors are currently clinical development; however, the predominant activity of most advanced these agents against insert domain (KDR), which compromises FGFR selectivity. Here, we report pharmacologic profile AZD4547, a novel selective inhibitor FGFR1, 2, 3 tyrosine kinases. AZD4547 inhibited recombinant vitro suppressed...
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 Background Camizestrant (C), a next-generation oral selective estrogen receptor (ER) antagonist and degrader (ngSERD) has shown promising clinical activity in ER+ breast cancer (BC) the Phase 1 SERENA-1 study1,2 with dose-dependent safety profile. The 2 randomized SERENA-2 study (NCT04214288) initially assessed three doses of C vs fulvestrant (F) post-menopausal women HER2˗ BC disease recurrence or progression after ≤1 endocrine therapy (ET) advanced setting. Methods evaluated...
Background SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in pre- and post-menopausal women with ER+, HER2− advanced breast cancer. Parts A B aim to determine the safety tolerability monotherapy define doses for clinical evaluation. Patients Methods Women aged 18 years or older metastatic recurrent cancer, refractory (or intolerant) therapy were assigned 25 mg up 450 once daily (QD; escalation) 75, 150, 300 QD (expansion). Safety tolerability, anti-tumor...
mTOR is an atypical serine threonine kinase involved in regulating major cellular functions, such as nutrients sensing, growth, and proliferation. part of the multiprotein complexes mTORC1 mTORC2, which have been shown to play critical yet functionally distinct roles regulation processes. Current clinical inhibitors only inhibit complex are derivatives macrolide rapamycin (rapalogs). Encouraging effects observed with rapalogs estrogen receptor-positive (ER(+)) breast cancer patients...
Herein we report the optimization of a series tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for treatment ER+ breast cancer. Structure based design together with systematic investigation each region molecular architecture led to identification N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated be highly potent SERD that...
Purpose: AZD9496 is an oral nonsteroidal, small-molecule inhibitor of estrogen receptor alpha (ERα) and a potent selective antagonist degrader ERα. This first-in-human phase I study determined the safety tolerability ascending doses in women with (ER)+/HER2- advanced breast cancer, characterized its pharmacokinetic (PK) profile, made preliminary assessment antitumor activity.Patients Methods: Forty-five patients received [20 mg once daily (QD) to 600 twice (BID)] dose-escalation,...
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...
To test the hypothesis that simultaneous, equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human 2), and erbB3 signaling, using novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro vivo.A range assays was used to model erbB family signaling homodimers heterodimers, including evaluation kinase activity, phosphorylation, proliferation cells, vivo testing a human tumor xenograft panel, with ex phosphorylation downstream...
1032 Background: SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in women with ER+, HER2− advanced breast cancer (ABC). Parts A/B (escalation/expansion) assessed monotherapy and have been presented previously. C/D examine combination palbociclib; here we present mature data from 75 mg being the dose currently under investigation 3 studies SERENA-4 (NCT04711252) SERENA-6 (NCT04964934). Methods: The primary objective was to determine safety tolerability once...
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...
Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor α (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, poor outcome. Phosphatase tensin homolog (PTEN), a negative regulator this pathway, typically lost ER-negative cancer. We set out to clarify role PTEN levels endocrine resistance, explore combination newly developed PI3K downstream kinase inhibitors overcome resistance. Altered cellular signaling, gene...
Abstract Purpose: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)–positive metastatic breast cancers include, among others, ER loss and acquired activating mutations the ligand-binding domain of gene (ESR1LBDm). ESR1 mutational mediated may be overcome by selective degraders (SERD). During first-in-human study oral SERD AZD9496, early changes circulating tumor cells (CTCs) DNA (ctDNA) were explored as potential noninvasive tools, alongside paired biopsies,...
1066 Background: Camizestrant, a next-generation oral selective estrogen receptor antagonist and degrader (ngSERD), was compared at two dose levels to fulvestrant 500 mg (F) in post-menopausal women with advanced ER+, HER2˗ breast cancer disease recurrence or progression after ≤1 endocrine therapy the setting Phase 2 randomized SERENA-2 study (NCT04214288). Camizestrant demonstrated statistically significant clinically meaningful benefit vs F progression-free survival (PFS) overall...
Herein, we report the optimization of a meta-substituted series selective estrogen receptor degrader (SERD) antagonists for treatment ER+ breast cancer. Structure-based design together with use modeling and NMR to favor bioactive conformation led highly potent basic SERDs promising physicochemical properties. Issues hERG activity resulted in strategy zwitterion formation ultimately identification 38. This compound was shown be SERD capable effectively degrading ERα both MCF-7 CAMA-1 cell...
Abstract Background: SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in women with ER+/HER2− advanced breast cancer. Data for as monotherapy and combination palbociclib or abemaciclib have been presented previously.1–3 Here we present data from parts I J (dose ranging expansion, respectively), which examined the pan-AKT inhibitor capivasertib. Methods: The primary objective was to determine safety tolerability 75 mg once daily (QD) capivasertib 400 twice...
Novel selective estrogen receptor degraders (SERDs) are a promising therapeutic option under investigation for patients with (ER)-positive/human epidermal growth factor 2 (HER2)-negative breast cancer. The efficacy of novel SERDs in the treatment advanced disease has prompted into their use early setting, to reduce cancer recurrence. Here, we describe design and rationale phase III, randomized, open-label CAMBRIA-1 CAMBRIA-2 studies. comparing next-generation oral SERD camizestrant versus...
ABSTRACT Epithelial cells within the mammary gland undergo developmental programmes of proliferation and apoptosis during pregnancy cycle. After weaning, secretory epithelial are removed by apoptosis. To determine whether members Bcl-2 gene family could be involved in regulating this process, we have examined changes their expression occur apoptotic program vivo. Bax Bcl-x were evenly expressed throughout development. However, Bak Bad was increased late lactation, proteins present time...
Abstract Epithelial cell survival is dependent on extracellular signals provided by both soluble factors and adhesion. In the mammary gland, extensive apoptosis of epithelial cells occurs rapidly when lactation ceases, but mechanism induction not known. tissue culture, require laminin as a ligand specific β1 integrins are necessary to suppress apoptosis. To explore possibility that dynamic changes in cell–matrix interactions contribute onset during involution vivo, detailed...