A5035968902- Lung Cancer Research Studies
- Microtubule and mitosis dynamics
- Cancer Mechanisms and Therapy
- Neuroendocrine Tumor Research Advances
- Peptidase Inhibition and Analysis
- Neuroblastoma Research and Treatments
- Cancer therapeutics and mechanisms
- Cancer-related Molecular Pathways
- Chronic Lymphocytic Leukemia Research
- Protein Degradation and Inhibitors
- Synthesis and Reactivity of Heterocycles
- PI3K/AKT/mTOR signaling in cancer
- Melanoma and MAPK Pathways
- Multiple Myeloma Research and Treatments
- Traditional and Medicinal Uses of Annonaceae
- Neuropeptides and Animal Physiology
- Lymphoma Diagnosis and Treatment
- Catalytic Alkyne Reactions
- Cancer, Hypoxia, and Metabolism
- Advanced Breast Cancer Therapies
- Synthetic Organic Chemistry Methods
- Receptor Mechanisms and Signaling
- Protein Tyrosine Phosphatases
- Regulation of Appetite and Obesity
- Antimicrobial Peptides and Activities
AstraZeneca (United Kingdom)
2002-2023
AstraZeneca (United States)
2014-2016
University of Bath
2003
University of Washington
1968
Proviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are overexpressed in several tumour types contribute to oncogenesis. AZD1208 is a potent ATP-competitive PIM kinase inhibitor investigated patients with recurrent or refractory acute myeloid leukaemia (AML) advanced solid tumours. Two dose-escalation studies were performed evaluate the safety tolerability, define maximum tolerated dose (MTD), of AML Secondary objectives pharmacokinetics, pharmacodynamics (PD) preliminary...
Abstract Background AZD2811 is a potent, selective Aurora kinase B inhibitor. We report the dose-escalation phase of first-in-human study assessing nanoparticle-encapsulated in advanced solid tumours. Methods was administered 12 cohorts (2-h intravenous infusion; 15‒600 mg; 21-/28-day cycles) with granulocyte colony-stimulating factor (G-CSF) at higher doses. The primary objective determining safety and maximum tolerated/recommended 2 dose (RP2D). Results Fifty-one patients received AZD2811....
Herein we report the optimization of a series pyrrolopyrimidine inhibitors interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify optimize our scaffold. Compound 28 demonstrated favorable physicochemical selectivity profile was identified as promising in vivo tool with which explore role IRAK4 inhibition treatment mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). shown be capable demonstrating NF-κB activation growth...
Neuropeptide Y (NPY) is thought to play a key role in stimulating feeding, thus making NPY receptors attractive appetite suppressant drug targets for treating obesity. Because the orexigenic effects of have been ascribed actions at Y5 receptor, we determined this receptor feeding rats, using small molecule antagonist receptor. NPY5RA-972 selective and potent (<10 nmol/l) antagonist. This compound central nervous system (CNS) penetrant, an oral dose 10 mg/kg rats produced concentrations...
Abstract Purpose: Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers response. Aurora kinase B (AURKB) inhibition exploits inherent genomic vulnerability SCLC a promising approach. Here, we identify response develop rational combinations with AURKB improve treatment efficacy....
The hypothesis that antagonists of the neuropeptide Y5 receptor would provide safe and effective appetite suppressants for treatment obesity has prompted vigorous research to identify suitable compounds. We discovered a series acylated aminocarbazole derivatives (e.g., 3a) are potent selective antagonists, representing interesting starting points but suffering from poor bioavailability concerns about potential toxicity as consequence embedded fragment. It proved relatively easy improve drug...
Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein TTK, are in different stages clinical development. However, cell response to SAC abrogation is poorly understood there no markers for patient selection.A panel 53 tumor lines origins was used. The effects drugs were analyzed by MTT flow cytometry. Copy number status determined FISH Q-PCR; mRNA expression nCounter RT-Q-PCR Western blotting. CRISPR-Cas9 technology used...
The synthesis of the core unit cycloaraneosene and ophiobolin M has been investigated, following a general strategy applicable to both 5−8 bicyclic systems. synthetic includes ring-closing metathesis reaction generate central eight-membered ring as well palladium-mediated coupling Grignard reagent introduce exocyclic side-chain. stereochemistry junction is also discussed moderate diastereoselectivity achieved. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)
The RAS-regulated RAF-MEK1/2-ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and frequently dysregulated human cancers, primarily by mutations BRAF or RAS genes. clinical benefit of inhibitors this as single agents has only been realized BRAF-mutant melanoma, with limited effect single-agent KRAS-mutant tumors. Combined inhibition multiple nodes within pathway, such MEK1/2 ERK1/2, may be necessary to effectively suppress tumors achieve meaningful benefit. Here, we report...
In a phase 1b study of acalabrutinib (a covalent Bruton tyrosine kinase (BTK) inhibitor) in combination with vistusertib dual mTORC1/2 patients relapsed/refractory diffuse large B-cell lymphoma (DLBCL), multiple ascending doses the as intermittent or continuous schedules were evaluated. The overall response rate was 12% (3/25). pharmacodynamic (PD) profile for showed that BTK occupancy all >95%. contrast, PD analysis variable inhibition phosphorylated 4EBP1 (p4EBP1) without modulation AKT...
<div>AbstractPurpose:<p>Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers response. Aurora kinase B (AURKB) inhibition exploits inherent genomic vulnerability SCLC a promising approach. Here, we identify response develop rational combinations with AURKB improve...
<p>Supplementary Figure 2 shows polyploidy and apoptosis are inhibited by high BCL2 levels</p>
<p>Supplementary Figure 1 shows BCL2 is a strong biomarker of resistance to AURK inhibition in SCLC.</p>
<p>Supplementary table shows AZD2811 sensitivity, transcriptomic and proteomic profiles of SCLC cell lines</p>
<div>Abstract<p>Purpose: Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers response. AURKB inhibition exploits inherent genomic vulnerability SCLC a promising approach. Here, we identify response develop rational combinations with improve treatment efficacy....
<p>Supplementary Figure 1 shows BCL2 is a strong biomarker of resistance to AURK inhibition in SCLC.</p>
<p>Supplementary Figure 2 shows polyploidy and apoptosis are inhibited by high BCL2 levels</p>
<p>Supplementary table shows AZD2811 sensitivity, transcriptomic and proteomic profiles of SCLC cell lines</p>
<p>Supplementary Figure 3 shows the combination of AZD2811 and BCL2 inhibitor enhances apoptosis cell death.</p>