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Your search keyword '"Betzi, Stéphane"' showing total 13 results
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13 results on '"Betzi, Stéphane"'

3. 4’-Ethynyl-2’-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress

Author

Calbert, Marissa L., primary, Chandramouly, Gurushankar, additional, Adams, Clare M., additional, Saez-Ayala, Magali, additional, Kent, Tatiana, additional, Tyagi, Mrityunjay, additional, Ayyadevara, V.S.S. Abhinav, additional, Wang, Yifan, additional, Krais, John J., additional, Gordon, John, additional, Atkins, Jessica, additional, Toma, Monika M., additional, Betzi, Stéphane, additional, Boghossian, Andrew S., additional, Rees, Matthew G., additional, Ronan, Melissa M., additional, Roth, Jennifer A., additional, Goldman, Aaron R., additional, Gorman, Nicole, additional, Mitra, Ramkrishna, additional, Childers, Wayne E., additional, Graña, Xavier, additional, Skorski, Tomasz, additional, Johnson, Neil, additional, Hurtz, Christian, additional, Morelli, Xavier, additional, Eischen, Christine M., additional, and Pomerantz, Richard T., additional

Published
2023
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4. From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia

Author

Saez-Ayala, Magali, primary, Hoffer, Laurent, additional, Abel, Sébastien, additional, Ben Yaala, Khaoula, additional, Sicard, Benoit, additional, Andrieu, Guillaume P., additional, Latiri, Mehdi, additional, Davison, Emma K., additional, Ciufolini, Marco A., additional, Brémond, Paul, additional, Rebuffet, Etienne, additional, Roche, Philippe, additional, Derviaux, Carine, additional, Voisset, Edwige, additional, Montersino, Camille, additional, Castellano, Remy, additional, Collette, Yves, additional, Asnafi, Vahid, additional, Betzi, Stéphane, additional, Dubreuil, Patrice, additional, Combes, Sébastien, additional, and Morelli, Xavier, additional

Published
2023
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5. Discovery of a PDZ Domain Inhibitor Targeting the Syndecan/Syntenin Protein–Protein Interaction: A Semi-Automated “Hit Identification-to-Optimization” Approach

Author

Hoffer, Laurent, primary, Garcia, Manon, additional, Leblanc, Raphael, additional, Feracci, Mikael, additional, Betzi, Stéphane, additional, Ben Yaala, Khaoula, additional, Daulat, Avais M., additional, Zimmermann, Pascale, additional, Roche, Philippe, additional, Barral, Karine, additional, and Morelli, Xavier, additional

Published
2023
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6. CRCM5484: A BET-BDII Selective Compound with Differential Anti-leukemic Drug Modulation

Author

Carrasco, Kendall, primary, Montersino, Camille, additional, Derviaux, Carine, additional, Saez-Ayala, Magali, additional, Hoffer, Laurent, additional, Restouin, Audrey, additional, Castellano, Rémy, additional, Casassa, Justine, additional, Roche, Philippe, additional, Pasquier, Eddy, additional, Combes, Sébastien, additional, Morelli, Xavier, additional, Collette, Yves, additional, and Betzi, Stéphane, additional

Published
2022
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7. CRCM5484: A BET- BDII Selective Compound With Differential Anti-Leukemic Drug Modulation

Author

Carrasco, Kendall, primary, Montersino, Camille, additional, Derviaux, Carine, additional, Saez-Ayala, Magali, additional, Hoffer, Laurent, additional, Restouin, Audrey, additional, Castellano, Rémy, additional, Casassa, Justine, additional, Roche, Philippe, additional, Pasquier, Eddy, additional, Combes, Sébastien, additional, Morelli, Xavier, additional, Collette, Yves, additional, and Betzi, Stéphane, additional

Published
2021
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11. Discovery of Small-Molecule Inhibitors of the PTK7/β-Catenin Interaction Targeting the Wnt Signaling Pathway in Colorectal Cancer

Author

Laetitia Ganier, Stephane Betzi, Carine Derviaux, Philippe Roche, Charlotte Dessaux, Christophe Muller, Laurent Hoffer, Xavier Morelli, Jean-Paul Borg, Betzi, Stéphane, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Universitaire de France (IUF), and Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.)

Subjects
Receptor Protein-Tyrosine Kinases, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, General Medicine, Biochemistry, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.CAN] Life Sciences [q-bio]/Cancer, Mutation, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Colorectal Neoplasms, Cell Adhesion Molecules, Wnt Signaling Pathway, beta Catenin, Cell Proliferation
Abstract

International audience; Second cause of death due to cancer worldwide, colorectal cancer (CRC) is a major public health issue. The discovery of new therapeutic targets is thus essential. The pseudokinase PTK7 intervenes in the regulation of the Wnt/βcatenin pathway signaling, in part, through a kinase-domain dependent interaction with the β-catenin protein. PTK7 is overexpressed in CRC; an event associated with metastatic development and reduced survival of non-metastatic patient. In addition, numerous alterations have been identified in CRC inducing constitutive activation of Wnt/β-catenin pathway signaling through β-catenin accumulation. Thus,targeting PTK7/β-catenin interaction could be of interest for future drug development. We have developed a NanoBRET TM screening assay recapitulating the interaction between PTK7 and βcatenin to identify compounds able to disrupt this protein-protein interaction. A high-throughput screening allowed us to identify small molecule inhibitors targeting the Wnt pathway signaling and inducing anti-proliferative and anti-tumor effect in vitro in CRC cells harboring β-catenin or APC mutations. Thus, inhibition of the PTK7/β-catenin interaction could represent a new therapeutic strategy to inhibit cell growth dependent on Wnt signaling pathway. Moreover, despite a lack of enzymatic activity of its tyrosine kinase domain, targeting the PTK7 kinase domain-dependent functions appears to be of interest for further therapeutic development.

Published
2022

12. CRCM5484: A BET- BDII Selective Compound With Differential Anti-Leukemic Drug Modulation

Author

Kendall Carrasco, Camille Montersino, Carine Derviaux, Magali Saez-Ayala, Laurent Hoffer, Audrey Restouin, Rémy Castellano, Justine Casassa, Philippe Roche, Eddy Pasquier, Sébastien Combes, Xavier Morelli, Yves Collette, Stéphane Betzi, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), and Betzi, Stéphane

Subjects
potentiation, diversity-oriented library, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], bone-marrow-derived stromal cell conditioned medium, Nuclear Proteins, Bromodomain, Cell Cycle Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, focused library, drug discovery, Small Molecule Libraries, protein-protein interaction, BDII selective inhibitor, Structure-Activity Relationship, modulation, Protein Domains, [SDV.CAN] Life Sciences [q-bio]/Cancer, hit-to-lead, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, optimization, Transcription Factors
Abstract

Differentially screening the Fr-PPIChem chemical library on the BET BRD4-BDII versus -BDI bromodomains led to the discovery of a BDII selective tetrahydropyridothienopyrimidinone (THPTP)-based compound. Structure-activity relationship (SAR) and hit-to-lead approaches allowed us to develop CRCM5484, a potent inhibitor of BET proteins with a preferential and 475-fold selectivity for the second bromodomain of the BRD3 protein (BRD3-BDII) over its first bromodomain (BRD3-BDI). Its very low activity was demonstrated in various cell-based assays, corresponding with recent data describing other selective BDII compounds. However, screening on a drug sensitivity and resistance-profiling platform revealed its ability to modulate the anti-leukemic activity in combination with various FDA-approved and/or in-development drugs in a cell- and context-dependent differential manner. Altogether, the results confirm the originality of the THPTP molecular mode of action in the BD cavity and its potential as starting scaffold for the development of potent and selective bromodomain inhibitors.

Published
2022

13. 4'-Ethynyl-2'-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress.

Author

Calbert ML, Chandramouly G, Adams CM, Saez-Ayala M, Kent T, Tyagi M, Ayyadevara VSSA, Wang Y, Krais JJ, Gordon J, Atkins J, Toma MM, Betzi S, Boghossian AS, Rees MG, Ronan MM, Roth JA, Goldman AR, Gorman N, Mitra R, Childers WE, Graña X, Skorski T, Johnson N, Hurtz C, Morelli X, Eischen CM, and Pomerantz RT

Subjects
Humans, Animals, Mice, Cell Line, Tumor, Lymphoma drug therapy, Lymphoma pathology, Lymphoma metabolism, Xenograft Model Antitumor Assays, Leukemia drug therapy, Leukemia pathology, Deoxycytidine Kinase metabolism, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacology
Abstract

Anticancer nucleosides are effective against solid tumors and hematologic malignancies, but typically are prone to nucleoside metabolism resistance mechanisms. Using a nucleoside-specific multiplexed high-throughput screening approach, we discovered 4'-ethynyl-2'-deoxycytidine (EdC) as a third-generation anticancer nucleoside prodrug with preferential activity against diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). EdC requires deoxycytidine kinase (DCK) phosphorylation for its activity and induces replication fork arrest and accumulation of cells in S-phase, indicating it acts as a chain terminator. A 2.1Å cocrystal structure of DCK bound to EdC and UDP reveals how the rigid 4'-alkyne of EdC fits within the active site of DCK. Remarkably, EdC was resistant to cytidine deamination and SAMHD1 metabolism mechanisms and exhibited higher potency against ALL compared with FDA-approved nelarabine. Finally, EdC was highly effective against DLBCL tumors and B-ALL in vivo. These data characterize EdC as a preclinical nucleoside prodrug candidate for DLBCL and ALL., (©2023 American Association for Cancer Research.)

Published
2024
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