A5082455051- Prostate Cancer Treatment and Research
- PARP inhibition in cancer therapy
- Protein Degradation and Inhibitors
- Cancer, Lipids, and Metabolism
- Lipid Membrane Structure and Behavior
- Heparin-Induced Thrombocytopenia and Thrombosis
- Platelet Disorders and Treatments
- Cancer-related gene regulation
- Force Microscopy Techniques and Applications
- CAR-T cell therapy research
- Cancer therapeutics and mechanisms
- Ubiquitin and proteasome pathways
- Computational Drug Discovery Methods
- Lipid metabolism and biosynthesis
- Proteoglycans and glycosaminoglycans research
- Immune Cell Function and Interaction
- Molecular Sensors and Ion Detection
- Integrated Circuits and Semiconductor Failure Analysis
- Animal testing and alternatives
- Cancer Immunotherapy and Biomarkers
- Lung Cancer Treatments and Mutations
- Synthesis and Biological Evaluation
- Antiplatelet Therapy and Cardiovascular Diseases
- thermodynamics and calorimetric analyses
- Photosynthetic Processes and Mechanisms
AstraZeneca (United Kingdom)
2021-2024
University of Nottingham
2013-2015
Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of (AR-SV). Inhibitors transcriptional coactivators that regulate activity, the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal cancer. Herein, we validate targeting p300/CBP as a strategy describe CCS1477, novel small-molecule inhibitor conserved bromodomain. We...
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...
The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is critical for platelet production and activation. Loss of results in severe macrothrombocytopenia, myelofibrosis aberrant function mice humans. Using a combination immunohistochemistry, affinity chromatography proteomics, we identified the extracellular matrix heparan sulfate (HS) proteoglycan perlecan as binding partner. Subsequent vitro biochemical studies cell-based genetic screen demonstrated that...
Casitas B-lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family RING finger E3 ubiquitin ligases, has been demonstrated to play central role in regulating effector T-cell function. Multiple studies using gene-targeting approaches have provided direct evidence that Cbl-b negatively regulates T, B, and NK cell activation via ubiquitin-mediated protein modulation. Thus, inhibition ligase activity can lead immune therapeutic potential immuno-oncology. Herein, we describe discovery...
11590 Background: Targeted degradation of androgen receptor (AR) and AR variants (ARV) remains an attractive therapeutic opportunity for patients with castrate resistant prostate cancer (CRPC). E1A binding protein (p300) CREB (CBP) are two closely related transcriptional activators AR. We have developed CCS1477 which is a potent, selective orally active small molecule inhibitor the bromodomain p300/CBP investigated its role in regulating expression function. Methods: Binding to p300, CBP...
ROS1 rearrangements account for 1–2% of non-small cell lung cancer patients, yet there are no specifically designed, selective therapies in the clinic. Previous knowledge potent inhibitors with selectivity over TrkA, a selected antitarget, enabled virtual screening as hit finding approach this project. The ligand-based was focused on identifying molecules similar 3D shape and pharmacophore to known actives. To that end, we turned AstraZeneca library, estimated cover 1015 synthesizable...
Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that responsible for repressing T-cell, natural killer (NK) cell, and B-cell activation. The robust antitumor activity observed in Cbl-b deficient mice arising from elevated T-cell NK-cell justified our discovery effort toward inhibitors might show therapeutic promise immuno-oncology, where activation of the immune system can drive recognition killing cancer cells. We undertook high-throughput screening campaign...
Modern drug discovery projects are plagued with high failure rate many of which have safety as the underlying cause. The process involves selecting right compounds from a...
The ability to target and control intermolecular interactions is crucial in the development of several different technologies. Here we offer a tool rationally design liquid media systems that can modulate specific interactions. This has broad implications deciphering nature forces complex solutions offers insight into govern both nonspecific binding given system. Nonspecific still continues be problem when dealing with analyte detection across range Here, exemplify on model membrane...
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,...
Abstract This white paper details the research conducted by Ignota Labs using their advanced causal and explainable AI technology, SAFEPATH , to analyse mechanisms of hepatotoxicity for two EGFR-TKI inhibitors, Erlotinib Gefitinib, latter having an as yet unknown mechanism toxicity. The known UGT1A1-mediated toxicity was recovered, a novel sphingolipid metabolism mechansim Gefitinib hypothesised subsequently experimentally validated. Crucially, we were also able suggest reason observed...
168 Background: Targeted degradation of androgen receptor (AR) and variants (ARV) remains an attractive therapeutic opportunity for patients with castrate resistant prostate cancer (CRPC). E1A binding protein (p300) CREB (CBP) are two closely related histone acetyl transferase proteins that act as transcriptional activators AR. We have developed potent, selective orally active small molecule inhibitors the bromodomain p300/CBP investigated their role in regulating expression function AR ARV....
We report details of the interaction sodium metasilicate with osteoblast cellular membranes using Fluoresceinphosphatidylethanolamine (FPE) as a fluorescent indicator membrane interactions. Fluorescence imaging studies FPE-based system revealed areas localized binding that would be consistent presence structure ‘receptor-like’ properties. From these results, it seems unlikely silica binds ‘non-specifically’ to surface. Moreover, receptors are into domains. Such regions cell could well...
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...
Abstract Background: E1A binding protein (p300) and CREB (CBP) are two closely related, paralogue histone acetyl transferase proteins that act as transcriptional co-activators of a variety cancer related genes. We have developed potent, selective orally active small molecule inhibitors the bromodomain p300/CBP investigated their role in regulating androgen receptor expression function. also examined driving synthetic lethality tumours. Loss function mutations either p300 or CBP (including...
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...
<div>Abstract<p>Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of (AR-SV). Inhibitors transcriptional coactivators that regulate activity, the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal cancer. Herein, we validate targeting p300/CBP as a strategy describe CCS1477, novel small-molecule inhibitor...
<p>Supplementary figures</p>
<p>Supplementary tables</p>
<p>Supplementary figures</p>
<div>Abstract<p>Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of (AR-SV). Inhibitors transcriptional coactivators that regulate activity, the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal cancer. Herein, we validate targeting p300/CBP as a strategy describe CCS1477, novel small-molecule inhibitor...
<p>Supplementary tables</p>