A5076814949- Protein Degradation and Inhibitors
- Adenosine and Purinergic Signaling
- Pharmacological Receptor Mechanisms and Effects
- Multiple Myeloma Research and Treatments
- Cancer, Stress, Anesthesia, and Immune Response
- Renal cell carcinoma treatment
- Histone Deacetylase Inhibitors Research
- Epigenetics and DNA Methylation
- Microtubule and mitosis dynamics
- Renal and related cancers
- Hedgehog Signaling Pathway Studies
- Cancer, Hypoxia, and Metabolism
- Peptidase Inhibition and Analysis
- Cancer-related gene regulation
- Cancer-related Molecular Pathways
- CAR-T cell therapy research
- Click Chemistry and Applications
- Chromatin Remodeling and Cancer
- Acute Myeloid Leukemia Research
- Cancer Immunotherapy and Biomarkers
- Ferroptosis and cancer prognosis
- Neuroblastoma Research and Treatments
- PARP inhibition in cancer therapy
- Receptor Mechanisms and Signaling
- ATP Synthase and ATPases Research
AstraZeneca (United States)
2015-2024
AstraZeneca (United Kingdom)
2013-2019
Kala Pharmaceuticals (United States)
2017
The University of Texas MD Anderson Cancer Center
2012
Northeastern University
2008
The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting bromodomains by small molecule inhibitors has proven be an effective means disrupt aberrant programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, orally available BET/BRD4 inhibitor possessing bivalent binding mode. Unlike previously described monovalent...
A series of dimeric compounds based on the AVPI motif Smac were designed and prepared as antagonists inhibitor apoptosis proteins (IAPs). Optimization cellular potency, physical properties, pharmacokinetic parameters led to identification compound 14 (AZD5582), which binds potently BIR3 domains cIAP1, cIAP2, XIAP (IC50 = 15, 21, 15 nM, respectively). This causes cIAP1 degradation induces in MDA-MB-231 breast cancer cell line at subnanomolar concentrations vitro. When administered...
KRAS mutation is present in approximately 30% of human lung adenocarcinomas. Although recent advances targeted therapy have shown great promise, effective targeting remains elusive, and concurrent alterations tumor suppressors render KRAS-mutant tumors even more resistant to existing therapies. Contributing the refractoriness are immunosuppressive mechanisms, such as increased presence suppressive regulatory T cells (Treg) elevated expression inhibitory receptor PD-1 on tumor-infiltrating...
Abstract Purpose: To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab patients advanced solid tumors. Patients and Methods: In phase Ia (dose escalation), had relapsed/refractory tumors; Ib expansion), checkpoint inhibitor–naïve metastatic castration-resistant prostate cancer (mCRPC) colorectal carcinoma, non–small cell lung prior anti–PD-1/PD-L1 exposure, other tumors (checkpoint-naïve exposure). received AZD4635 (75–200 mg once daily...
Abstract Purpose: The Hedgehog (Hh) pathway has emerged as an important in multiple tumor types and is thought to be dependent on a paracrine signaling mechanism. purpose of this study was determine the role pancreatic cancer-associated fibroblasts (human stellate cells, HPSCs) Hh signaling. In addition, we evaluated efficacy novel antagonist, AZD8542, progression with emphasis stroma compartment. Experimental Design: Expression members activation were analyzed both HPSCs cancer cells. We...
Here we report the discovery and optimization of a series bivalent bromodomain extraterminal inhibitors. Starting with observation BRD4 activity compounds from previous program, were optimized for potency physical properties. The compound this campaign exhibited excellent pharmacokinetic profile high in vitro vivo effecting c-Myc downregulation tumor growth inhibition xenograft studies. This was selected as development candidate, AZD5153. showed enhanced result binding clear correlation...
Abstract Purpose: Papillary renal cell carcinoma (PRCC) is the second most common cancer of kidney and carries a poor prognosis for patients with nonlocalized disease. The HGF receptor MET plays central role in PRCC aberrations, either through mutation, copy number gain, or trisomy chromosome 7 occurring majority cases. development effective therapies has been hampered part by lack available preclinical models. We determined pharmacodynamic antitumor response selective inhibitor AZD6094 two...
T cell effector functions contribute to the pathogenesis of rheumatoid arthritis. PKC-theta transduces signal from TCR through activation transcription factors NF-kappaB, AP-1, and NFAT. We examined effects deficiency on two Th1-dependent models Ag-induced arthritis found that PKC-theta-deficient mice develop disease, but at a significantly diminished severity compared with wild-type mice. In methylated BSA model, cellular infiltrates articular cartilage damage were mild in as Quantitation...
BRD4 is a transcriptional co-activator functioning to recruit regulatory complexes acetylated chromatin. A subset of High-grade Serous Ovarian Cancer (HGSOC) patients are typified by focal, recurrent gene amplifications. Despite previously described cancer dependencies, it unclear whether amplification events oncogenic in HGSOC. We find that physiologically relevant levels expression isoforms non-transformed ovarian cells result cellular transformation. Transcriptional profiling...
Abstract AZD5153, a reversible, bivalent inhibitor of the bromodomain and extraterminal family protein BRD4, has preclinical activity in multiple tumors. This first-in-human, phase I study investigated AZD5153 alone or with olaparib patients relapsed/refractory solid tumors lymphoma. Adults relapsed intolerant of, refractory to, prior therapies received escalating doses oral once daily twice continuously (21-day cycles), daily/twice intermittently plus 300 mg daily, until disease progression...
Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or T790M resistance mutations. While patients treated osimertinib show clinical benefit, disease progression and drug common. Emergence of de novo acquired from a tolerant persister (DTP) population is one mechanism proposed to explain on other targeted therapies. Here we profiled DTPs using RNA-seq...
Abstract Background Inhibition of the adenosine 2A receptor (A R) diminishes immunosuppressive effects and may complement immune-targeting drugs. This phase 2 study evaluated A R antagonist AZD4635 in combination with durvalumab or oleclumab patients metastatic castration-resistant prostate cancer. Methods Patients histologically/cytologically confirmed disease progressing within 6 months on ≥ therapy lines were randomly assigned to either Module 1 (AZD4635 + durvalumab) oleclumab). Primary...
Barasertib (AZD1152), a highly potent and selective aurora kinase B inhibitor, gave promising clinical activity in elderly acute myeloid leukemia (AML) patients. However, utility was limited by the requirement for 7-day infusion. Here we assessed potential of nanoparticle formulation Aurora inhibitor AZD2811 (formerly known as AZD1152-hQPA) preclinical models AML. When administered to HL-60 tumor xenografts at single dose between 25 98.7 mg/kg, treatment delivered profound inhibition growth,...
B-cell receptor (BCR) signaling is essential for the diffuse large lymphoma (DLBCL) subtype that originates from activated B-cells (ABCs). ABC-DLBCL cells are sensitive to Bruton tyrosine kinase intervention. However, patients with relapsed or refractory had overall response rates 33% 37% inhibitors, suggesting evaluation of combination-based treatment improved efficacy. We investigated efficacy and mechanism bromodomain extraterminal motif (BET) inhibitor AZD5153 combined acalabrutinib in...
In this study, we report a plasma proteomic analysis of mouse MCF7 xenograft, using novel platform named M-LAC (multilectin affinity chromatography), in an attempt to identify putative serum biomarkers tumor presence and response therapy. The use the enabled us focus on secreted proteins as well remove interference from albumin other nonglycosylated proteins. study focused human xenograft model which distinguish (human peptide sequences) host-derived murine proteins, potentially...
// Jai-Hee Moon 1, 2, * , Jae-Sik Shin Seung-Woo Hong Soo-A Jung 2 Ih-Yeon Hwang Jeong Hee Kim Eun Kyoung Choi Seung-Hee Ha Jin-Sun 5 Kyoung-Mok 6 Dae-Won Daejin 7 Yeong Seok Kyu-Pyo Yong Sang Kyung 3 Lee Maureen Hattersley 8 Dong-Hoon Jin 4 Tae Won 1 Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College Medicine, Medical Center, Songpa-gu, Seoul, Republic Korea Department Oncology, Radiation Convergence Internal Anatomy, Inje Busanjin-ku, Busan, Oncology...
Abstract Purpose: AZD5153 is a novel BRD4/BET inhibitor with distinctive bivalent bromodomain binding mode. To support its clinical development, we identified pharmacodynamic (PD) biomarkers for use in trials to establish target engagement. Experimental Design: CCR2 and CD180 mRNAs, initially from whole transcriptome profiling, were further evaluated by quantitative PCR hematologic cell lines, xenografts, blood rat, healthy volunteers, patients cancer. MYC HEXIM1 mRNAs also evaluated....
3085 Background: BRD4 is a bromodomain and extraterminal (BET) protein that regulates oncogenic programs by modifying gene transcription additional mechanisms. AZD5153 novel, reversible inhibitor with bivalent mechanism of action enhanced antitumor activity in preclinical models. This phase 1, multicenter, dose escalation study (NCT03205176) assesses AZD5153’s safety, pharmacokinetics (PK), pharmacodynamics (PD). We report here preliminary, unvalidated data from monotherapy pts RR solid...
TPS3179 Background: Protein arginine methyltransferase 5 (PRMT5) is an epigenetic enzyme that catalyzes symmetric dimethylation of substrates, regulating multiple cell processes. Deletion the methylthioadenosine phosphorylase gene MTAP in tumor cells results accumulation metabolite (MTA), a partial inhibitor PRMT5, potentially rendering susceptible to further PRMT5 targeting. Clinical activity first-generation, non-selective inhibitors (PRMT5i) limited by bone marrow toxicity due lack...