A5066191804- PARP inhibition in cancer therapy
- Phytochemicals and Medicinal Plants
- Toxin Mechanisms and Immunotoxins
- Computational Drug Discovery Methods
- DNA Repair Mechanisms
- Cardiac electrophysiology and arrhythmias
- Cell Image Analysis Techniques
- Ion channel regulation and function
- Integrated Circuits and Semiconductor Failure Analysis
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Lung Cancer Treatments and Mutations
- CRISPR and Genetic Engineering
- HER2/EGFR in Cancer Research
- Business and Economic Development
- Pluripotent Stem Cells Research
- Animal testing and alternatives
- Amino Acid Enzymes and Metabolism
- Global Healthcare and Medical Tourism
- Advanced Electron Microscopy Techniques and Applications
- Single-cell and spatial transcriptomics
- Click Chemistry and Applications
- Cancer therapeutics and mechanisms
- Childhood Cancer Survivors' Quality of Life
- Lung Cancer Research Studies
AstraZeneca (United Kingdom)
2015-2024
University of Ulster
2022
Saffron Walden Museum
2022
Belfast City Hospital
2022
Belfast Health and Social Care Trust
2022
Abstract Purpose: We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed selectivity over PARP2, which has been shown play a role in the survival hematopoietic/stem progenitor cells animal models. developed AZD5305 with aim achieving improved clinical efficacy wider therapeutic window. This next-generation PARP inhibitor (PARPi) could provide paradigm shift outcomes achieved by first-generation PARPi,...
A high-throughput phenotypic screen based on a Citrobacter freundii AmpC reporter expressed in Escherichia coli was executed to discover novel inhibitors of bacterial cell wall synthesis, an attractive, well-validated target for antibiotic intervention. Here we describe the discovery and characterization sulfonyl piperazine pyrazole compounds, each with mechanisms action. E. mutants resistant these compounds display no cross-resistance antibiotics other classes. Resistance maps LpxH, which...
Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some failed combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP lack selectivity PARP1 over PARP2 and other 16 family members, we hypothesized that this could contribute toxicity. Recent literature has demonstrated inhibition PARP1–DNA trapping are...
Hyperpolarizing GABAAR currents, the unitary events that underlie synaptic inhibition, are dependent upon efficient Cl− extrusion, a process is facilitated by neuronal specific K+/Cl− co-transporter KCC2. Its activity also determinant of anticonvulsant efficacy canonical GABAAR-positive allosteric: benzodiazepines (BDZs). Compromised KCC2 implicated in pathophysiology status epilepticus (SE), medical emergency rapidly becomes refractory to BDZ (BDZ-RSE). Here, we have identified small...
Abstract Purpose: We evaluated the properties and activity of AZD9574, a blood–brain barrier (BBB) penetrant selective inhibitor PARP1, assessed its efficacy safety alone in combination with temozolomide (TMZ) preclinical models. Experimental Design: AZD9574 was interrogated vitro for selectivity, PARylation inhibition, PARP-DNA trapping, ability to cross BBB, potential inhibit cancer cell proliferation. In vivo determined using subcutaneous as well intracranial mouse xenograft Mouse, rat,...
Herein, we report the identification and optimization of a series potent inhibitors EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations structure-based drug design (SBDD), tactical linker replacement led to selective molecules ultimately discovery 36. Compound 36 is inhibitor has demonstrated encouraging efficacy in NSCLC CRISPR-engineered H2073 xenografts that carry an SVD insertion reduced xenograft model...
While mechanisms of cytotoxicity and cytostaticity have been studied extensively from the biological side, relatively little is currently understood regarding areas chemical space leading to cytostasis in large compound collections. Predicting rationalizing potential adverse mechanism-of-actions (MoAs) small molecules however crucial for screening library design, given link even low level events observed man. In this study, we analyzed results a cell-based cascade, comprising 296 970...
PRMT5, a type 2 arginine methyltransferase, has critical role in regulating cell growth and survival cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel "MTA-cooperative" compounds identified through high-throughput biochemical screening approach. Optimization hits was achieved structure-based design with focus on improvement oral drug-like properties. Bioisosteric replacement original thiazole...
Cell-based assays have long been important within hit discovery paradigms; however, improving the disease relevance of assay system can positively affect translation small-molecule drug discovery, especially if adopted in initial identification assay. Consequently, there is an increasing need for disease-relevant systems capable running at large scale, including use induced pluripotent stem cells and donor-derived primary cells. Major hurdles to adopting these high-throughput screening are...
Herein, we report the optimization of a series epidermal growth factor receptor (EGFR) Exon20 insertion (Ex20Ins) inhibitors using structure-based drug design (SBDD), leading to discovery compound
Quantitative real-time polymerase chain reaction (PCR) is regarded as the gold standard for molecular profiling and target identification, but not in context of high-throughput screening owing to limitations on workflow, cost reagents, miniaturization opportunities. Recent advances have moved reverse transcription quantitative PCR (RT-qPCR) forward, such improvements liquid handling, launch higher throughput platforms, release one-step products. These reagents enable user go straight from a...
Target engagement by small molecules is necessary for producing a physiological outcome. In the past, lot of emphasis was placed on understanding thermodynamics such interactions to guide structure-activity relationships. It becoming clearer, however, that kinetics interaction between small-molecule inhibitor and biological target [structure-kinetic relationship (SKR)] critical selection optimum candidate drug molecule clinical trial. However, acquisition kinetic data in high-throughput...
PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their lies their ability trap DNA; however, were not strictly optimized for trapping nor selectivity among enzyme family. Previously we described second-generation inhibitor AZD5305, a selective PARP1-DNA trapper. AZD5305 maintained antitumor efficacy while exhibiting lower hematological toxicity. Recently,...
<p>Supplementary methods, figures, tables</p>
<div>AbstractPurpose:<p>We evaluated the properties and activity of AZD9574, a blood–brain barrier (BBB) penetrant selective inhibitor PARP1, assessed its efficacy safety alone in combination with temozolomide (TMZ) preclinical models.</p>Experimental Design:<p>AZD9574 was interrogated <i>in vitro</i> for selectivity, PARylation inhibition, PARP-DNA trapping, ability to cross BBB, potential inhibit cancer cell proliferation. <i>In vivo</i>...
<p>Supplementary methods, figures, tables</p>
<div>AbstractPurpose:<p>We evaluated the properties and activity of AZD9574, a blood–brain barrier (BBB) penetrant selective inhibitor PARP1, assessed its efficacy safety alone in combination with temozolomide (TMZ) preclinical models.</p>Experimental Design:<p>AZD9574 was interrogated <i>in vitro</i> for selectivity, PARylation inhibition, PARP-DNA trapping, ability to cross BBB, potential inhibit cancer cell proliferation. <i>In vivo</i>...
Abstract Since the approval of olaparib in 2014 for BRCA mutated (BRCAm) ovarian cancer, many PARP inhibitors have been developed and seen widespread success. However, as a class, these drugs are not without adverse events which limited their ability to be combined with chemotherapy. Most first generation were optimized before concept PARP1-DNA trapping was discovered mechanism by exert synthetic lethal effects on BRCAm cells. Moreover, selectivity across family potentially driving...
Target engagement by small-molecules is necessary for producing a physiological outcome. In the past, lot of emphasis was placed on understanding thermodynamics such interactions to guide structure-activity relationship. However, it becoming clearer that kinetics interaction between small molecule inhibitor and biological target (structure kinetic relationship, SKR) critical selection optimum candidate drug clinical trial. acquisition data in high-throughput manner using traditional methods...
Abstract PARP inhibitors exploit defects in DNA repair pathways to selectively target cancerous cells via PARP1 catalytic inhibition and trapping onto the DNA. All known clinical bind at same site center of enzyme. However, despite this resemblance they show immensely different outcomes terms response rate clinic due their varying degree ability. Moreover, first-generation were not optimized for selectivity across family potentially driving undesirable side effects, including intestinal...