Global ETD Search

1	Hypoxia-responsive prodrug of ATR inhibitor, AZD6738, selectively eradicates treatment-resistant cancer cells Barnieh, Francis M., Morais, Goreti R., Loadman, Paul, Falconer, Robert A., El-Khamisy, Sherif 08 July 2024 (has links) Yes / Targeted therapy remains the future of anti-cancer drug development, owing to the lack of specificity of current treatments which lead to damage in healthy normal tissues. ATR inhibitors have in recent times demonstrated promising clinical potential, and are currently being evaluated in the clinic. However, despite the considerable optimism for clinical success of these inhibitors, reports of associated normal tissues toxicities remain a concern and can compromise their utility. Here, ICT10336 is reported, a newly developed hypoxia-responsive prodrug of ATR inhibitor, AZD6738, which is hypoxia-activated and specifically releases AZD6738 only in hypoxic conditions, in vitro. This hypoxia-selective release of AZD6738 inhibited ATR activation (T1989 and S428 phosphorylation) and subsequently abrogated HIF1a-mediated adaptation of hypoxic cancers cells, thus selectively inducing cell death in 2D and 3D cancer models. Importantly, in normal tissues, ICT10336 is demonstrated to be metabolically stable and less toxic to normal cells than its active parent agent, AZD6738. In addition, ICT10336 exhibited a superior and efficient multicellular penetration ability in 3D tumor models, and selectively eradicated cells at the hypoxic core compared to AZD6738. In summary, the preclinical data demonstrate a new strategy of tumor-targeted delivery of ATR inhibitors with significant potential of enhancing the therapeutic index. / UoB STARTER Fellowship Award ATR AZD6738 DNA repair Hypoxia Prodrugs Targeted delivery
2	Development of novel tumour-activated peptide prodrugs of ATR/ATM inhibitor, AZD6738 Barnieh, Francis M. January 2019 (has links) The full text will be available at the end of the embargo period: 3rd April 2025 / The author's name as given on this thesis is Francis MPRAH BARNIEH. His publications use the name format Francis M. Barnieh. Prodrug Peptide Tumour ATM ATR AZD6738 Tumour-activated peptide prodrugs Cancer
3	Targeted delivery of a colchicine analogue provides synergy with ATR inhibition in cancer cells Barnieh, Francis M., Morais, Goreti R., Garland, Herbie, Loadman, Paul, Falconer, Robert A. 05 October 2023 (has links) Yes / Despite significant preclinical promise as anticancer agents, vascular-disrupting agents have yet to fulfil their clinical potential due to systemic toxicities. ICT2588 is a tumour-selective MT1-MMP-targeted prodrug of azademethylcolchicine, ICT2552. We investigate activation of ICT2588 and subsequent release of ICT2552 in tumour cells, and examine its ability to induce G2/M cell cycle arrest. We also explore synergism between ICT2588 and ATR inhibition, since colchicine, in addition to its vascular-disrupting properties, is known to induce G2/M arrest, DNA damage, and trigger apoptosis. Several ATR inhibitors are currently undergoing clinical evaluation. The cellular activation of ICT2588 was observed to correlate with MT1-MMP expression, with selective release of ICT2552 not compromised by cellular uptake and prodrug activation mechanisms. ICT2588 induced G2/M arrest, and triggered apoptosis in MT1-MMP-expressing cells, but not in cells lacking MT1-MMP expression, while ICT2552 itself induced G2/M arrest and triggered apoptosis in both cell lines. Interestingly, we uncovered that the intracellular release and accumulation dynamics of ICT2552 subsequent to prodrug activation provided synergism with an ATR inhibitor in a way not observed with direct administration of ICT2552. These findings have important potential implications for clinical combinations of ICT2588 and DNA repair inhibitors. Colchicine ICT2588 AZD6738 (Ceralasertib) VDA (Vascular disrupting agent) Anticancer agents Cancer cells
4	Functions of ATR Kinase in Terminally Differentiated Human Epidermal Keratinocyles and in Human Ex-Vivo Skin After Exposure to Ultraviolet B Radiation Gogusetti, Vivek Shashank Nag 02 June 2021 (has links) No description available. Aging Atmosphere Atmospheric Sciences Biomedical Research Climate Change Clinical Psychology Environmental Science Environmental Studies Health Care Health Education Health Sciences Medicine Molecular Biology Oncology Pharmaceuticals Pharmacology Pharmacy Sciences Toxicology DNA DAMAGE Cancer UVB Radiation Oncology DNA ATR kinase non-replicating cells differentiation neuroscience non-dividing post mitotic cells NTERTS Human skin Sun rays ATR inhibitor AZD6738 VE821

1

Page generated in 0.0304 seconds