A5073679081- Adenosine and Purinergic Signaling
- Synthesis and Biological Evaluation
- Cancer Immunotherapy and Biomarkers
- Pneumocystis jirovecii pneumonia detection and treatment
- Protein Kinase Regulation and GTPase Signaling
- PI3K/AKT/mTOR signaling in cancer
- Cancer-related Molecular Pathways
- Cancer Research and Treatments
- Phagocytosis and Immune Regulation
- Cytokine Signaling Pathways and Interactions
- Click Chemistry and Applications
- Cancer Mechanisms and Therapy
- Biochemical and Molecular Research
- CAR-T cell therapy research
- Monoclonal and Polyclonal Antibodies Research
- Nanoplatforms for cancer theranostics
- Receptor Mechanisms and Signaling
- Cancer, Hypoxia, and Metabolism
- Chronic Lymphocytic Leukemia Research
- Melanoma and MAPK Pathways
- Metabolomics and Mass Spectrometry Studies
- Neuropeptides and Animal Physiology
- Enzyme function and inhibition
- Ubiquitin and proteasome pathways
- Immunotherapy and Immune Responses
Biolog (United States)
2019
Amgen (United States)
2006-2011
University of Bristol
1993-1996
University of North Carolina at Chapel Hill
1968
It has been proposed previously that the sustained activation of mitogen‐activated protein kinase may be necessary for differentiation PC12 cells. Differentiation cells is induced by many extracellular agonists including nerve growth factor (NGF) and cyclicAMP analogues, but not epidermal (EGF), insulin or phorbol esters. Our results demonstrate that: (i) 8‐(4‐chlorophenylthio)‐cyclicAMP (CPT‐cAMP) activates MAP kinase; this raises possibility pathway activated agents act through adenylate...
Extracellular adenosine (ADO), present in high concentrations the tumor microenvironment (TME), suppresses immune function via inhibition of T cell and NK activation. Intratumoral generation ADO depends on sequential catabolism ATP by two ecto-nucleotidases, CD39 (ATP → AMP) CD73 (AMP ADO). Inhibition eliminates a major pathway production TME can reverse ADO-mediated suppression. Extensive interrogation structure–activity relationships (SARs), structure-based drug design, optimization...
We recently reported the initiation of a Phase I clinical trial with AB680, potent human CD73 inhibitor, being developed for treatment solid tumors (NCT03677973). undertook detailed kinetic analysis interaction between and AB680 to determine mode inhibition. found be reversible, slow-onset competitive inhibitor Ki 5 pM. Clinical candidates this potency are uncommon deserve special consideration during lead optimization.
CD73 is an extracellular mediator of purinergic signaling. When upregulated in the tumor microenvironment, has been implicated inhibition immune function through overproduction adenosine. Traditional efforts to inhibit have involved antibody therapy or development small molecules, most potent which mimic acidic and ionizable structure enzyme's natural substrate, adenosine 5'-monophosphate (AMP). Here, we report systematic discovery a novel class non-nucleotide inhibitors that are more than...
Abstract T cells play a critical role in the control of cancer. The development immune checkpoint blockers (ICB) aimed at enhancing antitumor T-cell responses has revolutionized cancer treatment. However, durable clinical benefit is observed only subset patients, prompting research efforts to focus on strategies that target multiple inhibitory signals within tumor microenvironment (TME) limit evasion and improve patient outcomes. Adenosine emerged as potent suppressant TME, CD73 major enzyme...
G-protein-coupled receptors (GPCRs) represent one of the largest gene families in human genome and have long been regarded as valuable targets for small-molecule drugs. The authors describe a new functional assay that directly monitors GPCR activation. It is based on interaction between beta-arrestin ligand-activated GPCRs uses enzyme fragment complementation technology. In this format, interest fused to small (approximately 4 kDa), optimized alpha peptide (termed ProLink) derived from...
✓ A case of cortical blindness after cerebral angiography is presented. Serial computerized tomography scans the brain revealed persistence contrast medium in occipital visual areas as well that may have been associated with “focal seizures” occurred angiography. This supports concept be secondary to direct effect on brain. The material was part due decreased renal function.
Solid tumors are often associated with high levels of extracellular ATP. Ectonucleotidases catalyze the sequential hydrolysis ATP to adenosine, which potently suppresses T-cell and NK-cell functions via adenosine receptors (A2a A2b). The ectonucleotidase CD73 catalyzes conversion AMP adenosine. Thus, increased enzymatic activity in tumor microenvironment is a potential mechanism for immune evasion has been poor prognosis clinic. inhibition anticipated restore function by skirting this major...
The selective inhibition of the lipid signaling enzyme PI3Kγ constitutes an opportunity to mediate immunosuppression and inflammation within tumor microenvironment but is difficult achieve due high sequence homology across class I PI3K isoforms. Here, we describe design a novel series potent inhibitors that attain isoform selectivity through divergent projection substituents into both “selectivity” “alkyl-induced” pockets adenosine triphosphate (ATP) binding site PI3Kγ. These efforts have...
Tyrosine kinase inhibitors have been widely used to probe the role of tyrosine phosphorylation in cellular signalling. These exhibit an apparent specificity for kinases over serine/threonine but little is known about their effects on other enzymes or biological systems. We demonstrate that genistein, erbstatin and alpha-cyanocinnamamides (tyrphostins) inhibitory fatty acid synthesis, lactate transport, mitochondrial oxidative aldehyde dehydrogenase. propose, therefore, results obtained using...
The successful application of immunotherapy in the treatment cancer relies on effective engagement immune cells tumor microenvironment. Phosphoinositide 3-kinase γ (PI3Kγ) is highly expressed tumor-associated macrophages, and its expression levels are associated with immunosuppression growth. Selective inhibition PI3Kγ offers a promising strategy immuno-oncology, which has led to development numerous potent inhibitors variable selectivity profiles. To facilitate further investigation...
Phosphoinositide-3-kinase γ (PI3Kγ) is highly expressed in immune cells and promotes the production migration of inflammatory mediators. The inhibition PI3Kγ has been shown to repolarize tumor microenvironment a more phenotype, thereby controlling suppression cancer. Herein, we report structure-based optimization an early lead series pyrazolopyrimidine isoindolinones, which culminated discovery potent isoform-selective inhibitors with favorable drug-like properties. X-ray cocrystal structure...
Interleukin 1 receptor activation innervates a cascade of signal transduction events that ultimately lead to the inflammatory and immune response genes. TRAF6 is Ub ligase (E3) involved in this pathway, inhibition critical enzyme may provide means for treating diseases. A TR-FRET assay has been developed evaluated HTS inhibitors. Bio-Ub Eu-Ub were polymerized presence activating E1, conjugating E2, TRAF6. Following 2-h incubation, reaction was stopped with buffer containing 10 m M EDTA...
A generic high-throughput screening assay based on the scintillation proximity technology has been developed for protein kinases. In this assay, biotinylated (33)P-peptide product is captured onto polylysine Ysi bead via avidin. The signal measuring formation increases linearly with avidin concentration due to effective capture of surface strong coulombic interactions. This novel optimized and validated in 384-well microplates. a pilot screen, signal-to-noise ratio 5- 9-fold Z' factor...
Treatment of CHO.T cells with either PMA or insulin led to the activation MAP kinase by ∼3‐fold, and p90 rsk ∼ 4‐fold. Over‐expression α, β I γ isoforms protein C caused a substantial enhancement effect on , however, was unchanged. ϵ isoform did not alter . The results suggest that isotypes γ, but ϵ, can mediate PMA, strongly support hypothesis initiate distinct signalling pathways.
Abstract Background: Adenosine production mediated by CD73 and/or TNAP is a potential mechanism of immune suppression across many cancer types. We have previously shown that AB928, dual A2aR/A2bR antagonist, in combination with anti-PD-1 or chemotherapy, rescues the immunosuppressive effects adenosine experimental tumor models. Oncogene-driven cancers are targeted specific tyrosine kinase inhibitors, typically leading to development several resistance mechanisms bypass signaling. These...
Abstract A hypoxic environment is a common characteristic of solid tumors. Cancer cells adapt to hypoxia and become more aggressive by up-regulation genes associated with metabolism, growth, proliferation, angiogenesis, erythropoiesis. Hypoxia-inducible factors (HIFs) are the central driving force for cellular response regulate vast array these genes. HIFs heterodimers composed an oxygen-sensitive HIF-α subunit (HIF-1α, HIF-2α, HIF-3α) constitutively expressed HIF-1β subunit. HIF-2α...
Introduction: It has been demonstrated that myeloid derived suppressor cells (MDSCs) have a direct role in tumor immune evasion, and increased MDSCs are associated with reduced overall survival several types of cancer. Elevated levels circulating shown to correlate blunted response checkpoint blockade. secrete arginase, which depletes arginine, leading decreased T cell activity suppressed anti-tumor response. Here we will present the characterization AB474, highly potent small molecule...