18 results on '"Radics G"'
Search Results
2. Supplementary Material for: Novel Iron-Whey Protein Microspheres Protect Gut Epithelial Cells from Iron-Related Oxidative Stress and Damage and Improve Iron Absorption in Fasting Adults
- Author
-
Wang, J., Radics, G., Whelehan, M., OʼDriscoll, A., Healy, A.M., Gilmer, J.F., and Ledwidge, M.
- Abstract
Background: Iron food fortification and oral iron formulations are frequently limited by poor absorption, resulting in the widespread use of high-dose oral iron, which is poorly tolerated. Methods: We evaluated novel iron-denatured whey protein (Iron-WP) microspheres on reactive oxygen species (ROS) and viability in gut epithelial (HT29) cells. We compared iron absorption from Iron-WP versus equimolar-dose (25 mg elemental iron) ferrous sulphate (FeSO4) in a prospective, randomised, cross-over study in fasting volunteers (n = 21 per group) dependent on relative iron depletion (a ferritin level ≤/>30 ng/mL). Results: Iron-WP caused less ROS generation and better HT29 cell viability than equimolar FeSO4. Iron-WP also showed better absorption with a maximal 149 ± 39% increase in serum iron compared to 65 ± 14% for FeSO4 (p = 0.01). The response to both treatments was dependent on relative iron depletion, and multi-variable analysis showed that better absorption with Iron-WP was independent of baseline serum iron, ferritin, transferrin saturation, and haemoglobin in the overall group and in the sub-cohort with relative iron depletion at baseline (p < 0.01). Conclusions: Novel Iron-WP microspheres may protect gut epithelial cells and improve the absorption of iron versus FeSO4. Further evaluation of this approach to food fortification and supplementation with iron is warranted.
- Published
- 2018
- Full Text
- View/download PDF
3. Structure of MBP-Mcl-1 in complex with compound 8b
- Author
-
Dokurno, P., primary, Szlavik, Z., additional, Ondi, L., additional, Csekei, M., additional, Paczal, A., additional, Szabo, Z.B., additional, Radics, G., additional, Murray, J., additional, Davidson, J., additional, Chen, I., additional, Davis, B., additional, Hubbard, R.E., additional, Pedder, C., additional, Surgenor, A.E., additional, Smith, J., additional, Robertson, A., additional, LeToumelin-Braizat, G., additional, Cauquil, N., additional, Zarka, M., additional, Demarles, D., additional, Perron-Sierra, F., additional, Geneste, O., additional, and Kotschy, A., additional
- Published
- 2019
- Full Text
- View/download PDF
4. Structure of MBP-Mcl-1 in complex with compound 7a
- Author
-
Dokurno, P., primary, Szlavik, Z., additional, Ondi, L., additional, Csekei, M., additional, Paczal, A., additional, Szabo, Z.B., additional, Radics, G., additional, Murray, J., additional, Davidson, J., additional, Chen, I., additional, Davis, B., additional, Hubbard, R.E., additional, Pedder, C., additional, Surgenor, A.E., additional, Smith, J., additional, Robertson, A., additional, LeToumelin-Braizat, G., additional, Cauquil, N., additional, Zarka, M., additional, Demarles, D., additional, Perron-Sierra, F., additional, Geneste, O., additional, and Kotschy, A., additional
- Published
- 2019
- Full Text
- View/download PDF
5. Structure of MBP-Mcl-1 in complex with compound 10d
- Author
-
Dokurno, P., primary, Szlavik, Z., additional, Ondi, L., additional, Csekei, M., additional, Paczal, A., additional, Szabo, Z.B., additional, Radics, G., additional, Murray, J., additional, Davidson, J., additional, Chen, I., additional, Davis, B., additional, Hubbard, R.E., additional, Pedder, C., additional, Surgenor, A.E., additional, Smith, J., additional, Robertson, A., additional, LeToumelin-Braizat, G., additional, Cauquil, N., additional, Zarka, M., additional, Demarles, D., additional, Perron-Sierra, F., additional, Geneste, O., additional, and Kotschy, A., additional
- Published
- 2019
- Full Text
- View/download PDF
6. Structure of Mcl-1 in complex with compound 13
- Author
-
Dokurno, P., primary, Szlavik, Z., additional, Ondi, L., additional, Csekei, M., additional, Paczal, A., additional, Szabo, Z.B., additional, Radics, G., additional, Murray, J., additional, Davidson, J., additional, Chen, I., additional, Davis, B., additional, Hubbard, R.E., additional, Pedder, C., additional, Surgenor, A.E., additional, Smith, J., additional, Robertson, A., additional, LeToumelin-Braizat, G., additional, Cauquil, N., additional, Zarka, M., additional, Demarles, D., additional, Perron-Sierra, F., additional, Geneste, O., additional, and Kotschy, A., additional
- Published
- 2019
- Full Text
- View/download PDF
7. Structure of Mcl-1 in complex with compound 8d
- Author
-
Dokurno, P., primary, Szlavik, Z., additional, Ondi, L., additional, Csekei, M., additional, Paczal, A., additional, Szabo, Z.B., additional, Radics, G., additional, Murray, J., additional, Davidson, J., additional, Chen, I., additional, Davis, B., additional, Hubbard, R.E., additional, Pedder, C., additional, Surgenor, A.E., additional, Smith, J., additional, Robertson, A., additional, LeToumelin-Braizat, G., additional, Cauquil, N., additional, Zarka, M., additional, Demarles, D., additional, Perron-Sierra, F., additional, Geneste, O., additional, and Kotschy, A., additional
- Published
- 2019
- Full Text
- View/download PDF
8. Structure of MBP-Mcl-1 in complex with compound 6a
- Author
-
Dokurno, P., primary, Szlavik, Z., additional, Ondi, L., additional, Csekei, M., additional, Paczal, A., additional, Szabo, Z.B., additional, Radics, G., additional, Murray, J., additional, Davidson, J., additional, Chen, I., additional, Davis, B., additional, Hubbard, R.E., additional, Pedder, C., additional, Surgenor, A.E., additional, Smith, J., additional, Robertson, A., additional, LeToumelin-Braizat, G., additional, Cauquil, N., additional, Zarka, M., additional, Demarles, D., additional, Perron-Sierra, F., additional, Geneste, O., additional, and Kotschy, A., additional
- Published
- 2019
- Full Text
- View/download PDF
9. Crystal structure of the MBP-MCL1 complex with highly selective and potent inhibitor of MCL1
- Author
-
Dokurno, P., primary, Kotschy, A., additional, Szlavik, Z., additional, Murray, J., additional, Davidson, J., additional, Csekei, M., additional, Paczal, A., additional, Szabo, Z., additional, Sipos, S., additional, Radics, G., additional, Proszenyak, A., additional, Balint, B., additional, Ondi, L., additional, Blasko, G., additional, Robertson, A., additional, Surgenor, A., additional, Chen, I., additional, Matassova, N., additional, Smith, J., additional, Pedder, C., additional, Graham, C., additional, and Geneste, O., additional
- Published
- 2016
- Full Text
- View/download PDF
10. Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor.
- Author
-
Szlavik Z, Csekei M, Paczal A, Szabo ZB, Sipos S, Radics G, Proszenyak A, Balint B, Murray J, Davidson J, Chen I, Dokurno P, Surgenor AE, Daniels ZM, Hubbard RE, Le Toumelin-Braizat G, Claperon A, Lysiak-Auvity G, Girard AM, Bruno A, Chanrion M, Colland F, Maragno AL, Demarles D, Geneste O, and Kotschy A
- Subjects
- Animals, Antineoplastic Agents pharmacology, Dose-Response Relationship, Drug, Female, HCT116 Cells, HeLa Cells, Humans, Mice, Mice, SCID, Protein Structure, Secondary, Protein Structure, Tertiary, Antineoplastic Agents chemistry, Drug Discovery methods, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Myeloid Cell Leukemia Sequence 1 Protein chemistry
- Abstract
Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.
- Published
- 2020
- Full Text
- View/download PDF
11. Structure-Guided Discovery of a Selective Mcl-1 Inhibitor with Cellular Activity.
- Author
-
Szlávik Z, Ondi L, Csékei M, Paczal A, Szabó ZB, Radics G, Murray J, Davidson J, Chen I, Davis B, Hubbard RE, Pedder C, Dokurno P, Surgenor A, Smith J, Robertson A, LeToumelin-Braizat G, Cauquil N, Zarka M, Demarles D, Perron-Sierra F, Claperon A, Colland F, Geneste O, and Kotschy A
- Subjects
- Cell Survival drug effects, HCT116 Cells, HeLa Cells, Humans, Protein Structure, Tertiary, Pyrimidines pharmacology, Structure-Activity Relationship, Thiophenes pharmacology, Cell Survival physiology, Drug Discovery methods, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Pyrimidines chemistry, Pyrimidines metabolism, Thiophenes chemistry, Thiophenes metabolism
- Abstract
Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.
- Published
- 2019
- Full Text
- View/download PDF
12. Novel Iron-Whey Protein Microspheres Protect Gut Epithelial Cells from Iron-Related Oxidative Stress and Damage and Improve Iron Absorption in Fasting Adults.
- Author
-
Wang J, Radics G, Whelehan M, OʼDriscoll A, Healy AM, Gilmer JF, and Ledwidge M
- Subjects
- Adult, Cross-Over Studies, Double-Blind Method, Drug Carriers administration & dosage, Epithelial Cells drug effects, Epithelial Cells metabolism, Fasting blood, Female, Ferritins blood, Humans, Intestinal Absorption drug effects, Iron adverse effects, Iron Deficiencies, Male, Microspheres, Oxidative Stress drug effects, Prospective Studies, Protective Agents administration & dosage, Iron administration & dosage, Whey Proteins administration & dosage
- Abstract
Background: Iron food fortification and oral iron formulations are frequently limited by poor absorption, resulting in the widespread use of high-dose oral iron, which is poorly tolerated., Methods: We evaluated novel iron-denatured whey protein (Iron-WP) microspheres on reactive oxygen species (ROS) and viability in gut epithelial (HT29) cells. We compared iron absorption from Iron-WP versus equimolar-dose (25 mg elemental iron) ferrous sulphate (FeSO4) in a prospective, randomised, cross-over study in fasting volunteers (n = 21 per group) dependent on relative iron depletion (a ferritin level ≤/>30 ng/mL)., Results: Iron-WP caused less ROS generation and better HT29 cell viability than equimolar FeSO4. Iron-WP also showed better absorption with a maximal 149 ± 39% increase in serum iron compared to 65 ± 14% for FeSO4 (p = 0.01). The response to both treatments was dependent on relative iron depletion, and multi-variable analysis showed that better absorption with Iron-WP was independent of baseline serum iron, ferritin, transferrin saturation, and haemoglobin in the overall group and in the sub-cohort with relative iron depletion at baseline (p < 0.01)., Conclusions: Novel Iron-WP microspheres may protect gut epithelial cells and improve the absorption of iron versus FeSO4. Further evaluation of this approach to food fortification and supplementation with iron is warranted., (© 2018 S. Karger AG, Basel.)
- Published
- 2017
- Full Text
- View/download PDF
13. A fluorescent analogue of tauroursodeoxycholic acid reduces ER stress and is cytoprotective.
- Author
-
Gavin J, Quilty F, Majer F, Gilsenan G, Byrne AM, Long A, Radics G, and Gilmer JF
- Subjects
- Animals, Endoplasmic Reticulum Chaperone BiP, Humans, Endoplasmic Reticulum Stress drug effects, Fluorescent Dyes chemistry, Taurochenodeoxycholic Acid pharmacology
- Abstract
Tauroursodeoxycholic acid (TUDCA) is a cytoprotective ER stress inhibitor and chemical chaperone. It has therapeutic potential in a wide array of diseases but a specific macromolecular target or molecular mechanism of action remains obscure. This Letter describes an effective new synthetic approach to taurine conjugation of bile acids which we used to prepare 3α-dansyl TUDCA (4) as a probe for TUDCA actions. As a model of ER stress we used the hepatocarcinoma cell line HUH7 and stimulation with either deoxycholic acid (DCA, 200μM) or tunicamycin (5μg/ml) and measured levels of Bip/GRP78, ATF4, CHOP and XBP1s/XBP1u. Compound 4 was more effective than UDCA at inhibiting ER stress markers and had similar effects to TUDCA. In a model of cholestasis using the cytotoxic DCA to induce apoptosis, pretreatment with 4 prevented cell death similarly to TUDCA whereas the unconjugated clinically used UDCA had no effect. 3α-Dansyl TUDCA (4) appears to be a suitable reporter for TUDCA effects on ER stress and related cytoprotective activity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
14. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models.
- Author
-
Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, Chanrion M, Kelly GL, Gong JN, Moujalled DM, Bruno A, Csekei M, Paczal A, Szabo ZB, Sipos S, Radics G, Proszenyak A, Balint B, Ondi L, Blasko G, Robertson A, Surgenor A, Dokurno P, Chen I, Matassova N, Smith J, Pedder C, Graham C, Studeny A, Lysiak-Auvity G, Girard AM, Gravé F, Segal D, Riffkin CD, Pomilio G, Galbraith LC, Aubrey BJ, Brennan MS, Herold MJ, Chang C, Guasconi G, Cauquil N, Melchiore F, Guigal-Stephan N, Lockhart B, Colland F, Hickman JA, Roberts AW, Huang DC, Wei AH, Strasser A, Lessene G, and Geneste O
- Subjects
- Animals, Antineoplastic Agents administration & dosage, Apoptosis drug effects, Cell Line, Tumor, Female, Humans, Leukemia drug therapy, Leukemia metabolism, Leukemia pathology, Lymphoma drug therapy, Lymphoma metabolism, Lymphoma pathology, Male, Mice, Models, Molecular, Multiple Myeloma drug therapy, Multiple Myeloma metabolism, Multiple Myeloma pathology, Myeloid Cell Leukemia Sequence 1 Protein chemistry, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Neoplasms metabolism, Pyrimidines administration & dosage, Thiophenes administration & dosage, Xenograft Model Antitumor Assays, bcl-2 Homologous Antagonist-Killer Protein metabolism, bcl-2-Associated X Protein metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Models, Biological, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Neoplasms drug therapy, Neoplasms pathology, Pyrimidines pharmacology, Pyrimidines therapeutic use, Thiophenes pharmacology, Thiophenes therapeutic use
- Abstract
Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.
- Published
- 2016
- Full Text
- View/download PDF
15. New highly toxic bile acids derived from deoxycholic acid, chenodeoxycholic acid and lithocholic acid.
- Author
-
Májer F, Sharma R, Mullins C, Keogh L, Phipps S, Duggan S, Kelleher D, Keely S, Long A, Radics G, Wang J, and Gilmer JF
- Subjects
- Apoptosis, Bile Acids and Salts pharmacology, Caco-2 Cells, Cell Survival, Chenodeoxycholic Acid pharmacology, Deoxycholic Acid pharmacology, Humans, Lithocholic Acid pharmacology, Ursodeoxycholic Acid pharmacology, Bile Acids and Salts metabolism, Chenodeoxycholic Acid metabolism, Deoxycholic Acid metabolism, Lithocholic Acid metabolism, Ursodeoxycholic Acid metabolism
- Abstract
We have prepared a new panel of 23 BA derivatives of DCA, chenodeoxycholic acid (CDCA) and lithocholic acid (LCA) in order to study the effect of dual substitution with 3-azido and 24-amidation, features individually associated with cytotoxicity in our previous work. The effect of the compounds on cell viability of HT-1080 and Caco-2 was studied using the 3-[4,5-dimethylthizol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Compounds with high potency towards reduction of cell viability were further studied using flow cytometry in order to understand the mechanism of cell death. Several compounds were identified with low micromolar IC₅₀ values for reducing cell viability in the Caco-2 and HT1080 cell lines, making them among the most potent BA apoptotic agents reported to date. There was no evidence of relationship between overall hydrophobicity and cytotoxicity supporting the idea that cell death induction by BAs may be structure-specific. Compounds derived from DCA caused cell death through apoptosis. There was some evidence of selectivity between the two cell lines studied which may be due to differing expression of CD95/FAS. The more toxic compounds increased ROS production in Caco-2 cells, and co-incubation with the antioxidant N-acetyl cysteine blunted pro-apoptotic effects. The properties these compounds suggest that there may be specific mechanism(s) mediating BA induced cell death. Compound 8 could be useful for investigating this phenomenon., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
16. Functionalization of carbon nanoparticles modulates inflammatory cell recruitment and NLRP3 inflammasome activation.
- Author
-
Yang M, Flavin K, Kopf I, Radics G, Hearnden CH, McManus GJ, Moran B, Villalta-Cerdas A, Echegoyen LA, Giordani S, and Lavelle EC
- Subjects
- Animals, Antigen-Presenting Cells, Caspase 1 metabolism, Dendritic Cells drug effects, Dose-Response Relationship, Drug, Female, Ligands, Macrophages drug effects, Mice, Mice, Inbred C57BL, Monocytes cytology, NLR Family, Pyrin Domain-Containing 3 Protein, Nanoparticles chemistry, Nanotechnology, Oxygen chemistry, Surface Properties, Carrier Proteins chemistry, Inflammation pathology, Nanotubes, Carbon chemistry
- Abstract
The inflammatory effects of carbon nanoparticles (NPs) are highly disputed. Here it is demonstrated that endotoxin-free preparations of raw carbon nanotubes (CNTs) are very limited in their capacity to promote inflammatory responses in vitro, as well as in vivo. Upon purification and selective oxidation of raw CNTs, a higher dispersibility is achieved in physiological solutions, but this process also enhances their inflammatory activity. In synergy with toll-like receptor (TLR) ligands, CNTs promote NLRP3 inflammasome activation and it is shown for the first time that this property extends to spherical carbon nano-onions (CNOs) of 6 nm in size. In contrast, the benzoic acid functionalization of purified CNTs and CNOs leads to significantly attenuated inflammatory properties. This is evidenced by a reduced secretion of the inflammatory cytokine IL-1β, and a pronounced decrease in the recruitment of neutrophils and monocytes following injection into mice. Collectively, these results reveal that the inflammatory properties of carbon NPs are highly dependent on their physicochemical characteristics and crucially, that chemical surface functionalization allows significant moderation of these properties., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2013
- Full Text
- View/download PDF
17. Design, synthesis, and pharmacological effects of a cyclization-activated steroid prodrug for colon targeting in inflammatory bowel disease.
- Author
-
Ruiz JF, Radics G, Windle H, Serra HO, Simplício AL, Kedziora K, Fallon PG, Kelleher DP, and Gilmer JF
- Subjects
- Animals, Bacteria metabolism, Colon microbiology, Cyclization, Drug Delivery Systems, Esters, Intestinal Absorption drug effects, Mice, Prodrugs chemistry, Prodrugs metabolism, Adrenal Cortex Hormones administration & dosage, Colon metabolism, Drug Carriers chemical synthesis, Inflammatory Bowel Diseases drug therapy, Prodrugs chemical synthesis
- Abstract
Glucocorticoids are used in the treatment of inflammatory bowel disease. A limitation to their use is that they undergo absorption from the GIT before reaching the colon causing severe systemic side effects. We report here on a novel prodrug approach to targeting corticosteroids to the colon. The design involves attaching a 21-ester group that suppresses absorption during transit to the colon. The prodrug is designed to be primed by colonic microflora liberating an amino ester that cyclizes releasing the steroid. One of the prodrugs 5b was as efficacious as prednisolone in the murine DSS model but did not cause thymic atrophy, a marker for systemic steroid effects.
- Published
- 2009
- Full Text
- View/download PDF
18. Fluoro-modified chemotactic peptides: fMLF analogues.
- Author
-
Koksch B, Dahl C, Radics G, Vocks A, Arnold K, Arnhold J, Sieler J, and Burger K
- Subjects
- Fluorescence, Humans, Kinetics, Magnetic Resonance Spectroscopy, Molecular Structure, N-Formylmethionine Leucyl-Phenylalanine chemical synthesis, N-Formylmethionine Leucyl-Phenylalanine chemistry, Neutrophils cytology, Neutrophils drug effects, Peptides chemical synthesis, Protein Structure, Tertiary, Chemotaxis drug effects, N-Formylmethionine Leucyl-Phenylalanine analogs & derivatives, N-Formylmethionine Leucyl-Phenylalanine pharmacology, Peptides chemistry, Peptides pharmacology
- Abstract
A small library of peptide analogues of the chemotactic tripeptide For-Met-Leu-Phe-NH2 modified by substitution of Leu at position 2 by three different fluorinated amino acids varying in content of fluorine, length of the fluorinated side chain, and alkylation degree at the alpha-carbon atom was synthesized. The influence of the fluorine substitution on the biological activity was investigated by measuring the oxidative activity of neutrophils using a luminol-dependent chemiluminescence assay.
- Published
- 2004
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.