A5084963518- Cytokine Signaling Pathways and Interactions
- RNA modifications and cancer
- Cancer Genomics and Diagnostics
- Immunodeficiency and Autoimmune Disorders
- Chronic Lymphocytic Leukemia Research
- CRISPR and Genetic Engineering
- Cytomegalovirus and herpesvirus research
- Cell death mechanisms and regulation
- Click Chemistry and Applications
- Immune Cell Function and Interaction
- Adenosine and Purinergic Signaling
- Patient Dignity and Privacy
- Fibroblast Growth Factor Research
- MRI in cancer diagnosis
- DNA Repair Mechanisms
- interferon and immune responses
- 3D Printing in Biomedical Research
- Multiple Myeloma Research and Treatments
- Histone Deacetylase Inhibitors Research
- Immune cells in cancer
- Vascular Malformations and Hemangiomas
- Cancer Cells and Metastasis
- MicroRNA in disease regulation
- Pluripotent Stem Cells Research
- Signaling Pathways in Disease
AstraZeneca (United States)
2012-2021
Kala Pharmaceuticals (United States)
2015-2017
Systemically administered antisense oligonucleotide AZD9150 inhibits STAT3 and shows anticancer activity in preclinical models patients.
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...
DNA damage checkpoint kinases ATR and WEE1 are among key regulators of response pathways protecting cells from replication stress, a hallmark cancer that has potential to be exploited for therapeutic use. inhibitors in early clinical trials success will require greater understanding both their mechanism action biomarkers patient selection. Here, we report selective antitumor activity subset non-germinal center B-cell (GCB) diffuse large lymphoma (DLBCL) cell lines, characterized by high MYC...
Abstract Purpose: Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2–selective inhibitor, had success the clinic, another member, Bcl-xL, also target and mechanism resistance. Therefore, we developed dual Bcl-2/Bcl-xL inhibitor that broadens therapeutic activity while minimizing Bcl-xL–mediated thrombocytopenia. Experimental Design: We used structure-based chemistry to design small-molecule Bcl-xL...
: PARP proteins represent a class of post-translational modification enzymes with diverse cellular functions. Targeting PARPs has proven to be efficacious clinically, but exploration the therapeutic potential inhibition been limited targeting poly(ADP-ribose) generating PARP, including PARP1/2/3 and tankyrases. The cancer-related functions mono(ADP-ribose) PARP6, remain largely uncharacterized. Here, we report novel strategy PARP6 using first reported inhibitors. By screening collection...
Structure-activity relationship analysis identified (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation monopolar phenotype characteristic KSP inhibition induction...
Jak1/2 inhibition suppresses STAT3 phosphorylation that is characteristic of many cancers. Activated promotes the transcription factors enhance tumor growth, survival, and angiogenesis. AZD1480 a novel small molecule inhibitor Jak1/2, which key mediator activation. This study examined use diffusion-weighted (DW) dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) biomarkers in assessing early response to AZD1480. Cediranib (AZD2171), vascular endothelial growth factor signaling...
AZD3229 demonstrates pan-KIT/PDGFRα activity in several preclinical models and is a promising agent for the treatment of GIST.
Abstract Adenosine signaling through the high affinity adenosine 2A receptor (A2AR) on immune cells elicits a range of immunosuppressive effects which can promote tumor growth and limit efficacy checkpoint inhibitors. AZD4635 (HTL-1071) is potent selective oral A2AR antagonist, currently in Phase 1 clinical trial as single agent combination with durvalumab (anti-PD-L1 Ab) patients solid malignancies. In functional vitro assays, IC50 for inhibition dependent concentrations ranges from 1,...
Abstract Genomic technologies have greatly expanded our understanding of cancer biology, although they not yet been effectively translated into improved therapeutics, partly due to the inability available therapeutic modalities target most promising driver pathways. In contrast other approaches, antisense technology allows rational design potent, sequence-specific inhibitors based on genome sequencing information alone. Recent human clinical data demonstrated potent activity oligonucleotides...
Abstract Next generation sequencing technologies have greatly expanded our understanding of cancer genomes, epigenomes and transcriptomes. This knowledge, however, has not yet been effectively translated into improved therapeutics, partly due to the inability available therapeutic modalities target most promising driver pathways. In contrast other approaches, druggable universe is limited with antisense technology as inhibitors can be rationally designed based on sequence information alone....
Abstract AZD9150 is a gen2.5 antisense oligonucleotide (ASO) targeting STAT3. Gen2.5 ASOs exhibit enhanced drug-like properties compared to previous generations of therapeutics, including increased stability and resistance nucleases, marked decrease in proinflammatory effects, potency. The immune suppressive effects STAT3 signaling are well established (Kortylewski et al.; Nat. Med. 2005 Curr. Opin. Immunol. 2008). Preclinical experiments were carried out determine the potential for...
Abstract AZD9150, a gen2.5 antisense oligonucleotide (ASO) targeting human STAT3, has improved drug-like properties compared to previous generation ASO therapeutics, including increased stability and resistance nucleases, reduced proinflammatory effects, enhanced potency. We have previously reported that in tumors, STAT3 ASOs are taken up preferentially stromal immune cells of the tumor microenvironment (TME). Since AZD9150 is selective for we used surrogate (muSTAT3 ASO) explore...
Abstract We have established a novel assay to assess circulating tumor DNA (ctDNA) in mice engrafted with disseminated cell line and patient-derived xenografts (PDX) of hematologic malignancies. Disseminated models recapitulate many features human disease, but engraftment multiple tissues makes monitoring disease treatment response difficult. Existing assays also lack the sensitivity required minimal residual (MRD). This ddPCR targets highly conserved human-specific regions LINE-1 HERV-K...