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18 results on '"MESH: Quinazolines"'

1. Identification of novel quinazoline derivatives as potent antiplasmodial agents

Author

Johan Schultz, Dany Pechalrieu, Sergio Valente, Anne Bouchut, Tina S. Skinner-Adams, Giancarlo Fabrizi, Paola B. Arimondo, Urban Hoglund, Katherine T. Andrews, Roberta Mazzone, Sophia Lafitte, Antonello Mai, Alessia Lucidi, Christine Pierrot, Ming Jang Chua, Jamal Khalife, Dante Rotili, Institut Pasteur de Lille, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] [UNIROMA], Pharmacochimie de la Régulation Epigénétique du Cancer [ETaC], Réseau International des Instituts Pasteur (RIIP), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Kancera AB [Sweden], Adlego Biomedical AB [Sweden], Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), GRIFFITH UNIVERSITY AUS, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), This work was supported by the Australian National Health and Medical Research Council (APP1074016 to K.T.A.), Italian PRIN 2016 (prot. 20152TE5PK to A.M.), AIRC 2016 (n. 19162 to A.M.), NIH (n. R01GM114306 to A.M.), Progetto Ateneo Sapienza 2017 (to D.R.), the A-ParaDDisE program funded under the European Union's Seventh Framework Programme (grant agreement no. 602080 to A.B., C.P., S.L., A.M., D.R., S.V., J.S., U.H., K.T.A. and J.K.) and Griffith University (GUIPRS and GUPRS scholarships to M.J.C.). We thank Mary Clarke (Griffith University) for technical assistance. We also thank the BioImaging Center Lille Facility for access to the BD FACSCanto II cytometer., European Project: 602080,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,A-PARADDISE(2014), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Griffith University [Brisbane], Centre d’Infection et d’Immunité de Lille (CIIL) - INSERM U1019 - UMR 9017 (CIIL), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Università degli Studi di Roma 'La Sapienza' [Rome], and PIERRE FABRE-Centre National de la Recherche Scientifique (CNRS)

Subjects
Plasmodium berghei, Molecular Conformation, Pharmacology, MESH: Parasitic Sensitivity Tests, 01 natural sciences, Antimalarial agents, MESH: Dose-Response Relationship, Drug, Mice, MESH: Structure-Activity Relationship, Parasitic Sensitivity Tests, PK studies, Histone deacetylase inhibitors, Drug Discovery, P. berghei mouse model, MESH: Animals, Antimalarial Agent, DNA methyltransferase inhibitors, Artemisinin, MESH: Plasmodium falciparum, media_common, 0303 health sciences, Mice, Inbred BALB C, biology, Chemistry, General Medicine, 3. Good health, MESH: Quinazolines, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, medicine.drug, Drug, antimalarial agents, histone deacetylase inhibitors, media_common.quotation_subject, Plasmodium falciparum, MESH: Mice, Inbred BALB C, Context (language use), 03 medical and health sciences, Antimalarials, Structure-Activity Relationship, In vivo, parasitic diseases, medicine, MESH: Plasmodium berghei, [CHIM]Chemical Sciences, Animals, Humans, MESH: Mice, 030304 developmental biology, MESH: Molecular Conformation, MESH: Humans, Dose-Response Relationship, Drug, 010405 organic chemistry, Organic Chemistry, Fibroblasts, biology.organism_classification, medicine.disease, MESH: Antimalarials, 0104 chemical sciences, MESH: Fibroblasts, Quinazolines, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Malaria
Abstract

International audience; Despite the recent reductions in the global burden of malaria, this disease remains a devastating cause of death in tropical and subtropical regions. As there is no broadly effective vaccine for malaria, prevention and treatment still rely on chemotherapy. Unfortunately, emerging resistance to the gold standard artemisinin combination therapies means that new drugs with novel modes of action are urgently needed. In this context, Plasmodium histone modifying enzymes have emerged as potential drug targets, prompting us to develop and optimize compounds directed against such epigenetic targets. A panel of 51 compounds designed to target different epigenetic enzymes were screened for activity against Plasmodium falciparum parasites. Based on in vitro activity against drug susceptible and drug-resistant P. falciparum lines, selectivity index criterion and favorable pharmacokinetic properties, four compounds, one HDAC inhibitor (1) and three DNMT inhibitors (37, 43 and 45), were selected for preclinical studies in a mouse model of malaria. In vivo data showed that 37, 43 and 45 exhibited oral efficacy in the mouse model of Plasmodium berghei infection. These compounds represent promising starting points for the development of novel antimalarial drugs.

Published
2019
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2. Long-Term Control of Hypercortisolism by Vandetanib in a Case of Medullary Thyroid Carcinoma with a Somatic RET Mutation

Author

Marie Bienvenu-Perrard, Anne-Cécile Paepegaey, Najiba Lahlou, Lionel Groussin, Estelle Louiset, Léopoldine Bricaire, Béatrix Cochand-Priollet, Marco Alifano, Nelly Burnichon, Pierre-Olivier Sarfati, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Différenciation et communication neuronale et neuroendocrine (DC2N), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, and Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Oncology, Hydrocortisone, MESH: Carcinoma, Neuroendocrine, Somatic cell, Endocrinology, Diabetes and Metabolism, Cushing's syndrome, Vandetanib, MESH: Cushing Syndrome, 0302 clinical medicine, Endocrinology, Piperidines, medullary thyroid carcinoma, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Protein Kinase Inhibitors, Cushing Syndrome, MESH: Middle Aged, Cytoreduction Surgical Procedures, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Debulking, MESH: Hydrocortisone, 3. Good health, MESH: Quinazolines, MESH: Piperidines, MESH: Thyroid Neoplasms, 030220 oncology & carcinogenesis, Thyroidectomy, Neck Dissection, Tyrosine kinase, Long term control, medicine.drug, Calcitonin, medicine.medical_specialty, vandetanib, Medullary cavity, 030209 endocrinology & metabolism, MESH: Proto-Oncogene Proteins c-ret, MESH: Thyroidectomy, Thyroid carcinoma, 03 medical and health sciences, Internal medicine, MESH: Neck Dissection, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, MESH: Cytoreduction Surgical Procedures, Thyroid Neoplasms, Protein Kinase Inhibitors, MESH: Humans, hypercortisolism, MESH: Calcitonin, business.industry, Proto-Oncogene Proteins c-ret, MESH: Male, Carcinoma, Neuroendocrine, Quinazolines, business, RET
Abstract

Medullary thyroid carcinomas (MTCs) complicated by ectopic Cushing's syndrome (CS) have a poor prognosis, partially due to the difficulty in controlling hypercortisolism by adrenal blocking drugs. Recent reports (including the initial follow-up of this patient) have suggested that tyrosine kinase inhibitors (TKIs) may be a therapeutic option due to an anti-secretory action on ACTH. However, there is a lack of long-term follow-up studies.The case is reported of a 58-year-old man with MTC-related CS resistant to a combination of several anti-cortisolic drugs. Vandetanib, an oral multi-TKI that targets RET in particular, was initiated, and a rapid reversal of the hypercortisolism was observed without any change in tumor size. Vandetanib was briefly interrupted twice, once for 45 days because of side effects and a second time for 10 days to schedule surgical debulking. Each time, plasma cortisol and calcitonin levels increased after TKI withdrawal and were rapidly lowered by vandetanib reintroduction. As described in other cases of CS caused by MTC, a marked ACTH increase after desmopressin stimulation was observed before vandetanib therapy. In contrast, a blunted ACTH response to desmopressin was documented throughout the course of vandetanib treatment. This modulation of the tumoral ACTH production is a strong argument in favor of a TKI anti-secretory action. A left thyroid lobectomy and a modified neck dissection were performed one year after the initiation of vandetanib in order to reduce the tumor mass. An activating M918T RET (c.2753TC) somatic mutation was identified in a lymph node metastasis.Three years and eight months after vandetanib initiation, there was no sign of recurrence of hypercortisolism. This case illustrates the long-term effectiveness of vandetanib in maintaining the control of hypercortisolism in MTC-related CS.

Published
2017
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3. Cost-effectiveness of three strategies for second-line erlotinib initiation in nonsmall-cell lung cancer: the ERMETIC study part 3

Author

Nicolas Richard, Pierre Hainaut, Bruno Coudert, Xavier Sastre-Garau, Jean-Luc Prétet, Yves-Marie ROBIN, Christos Chouaid, Stefan Michiels, Pierre-Emmanuel Falcoz, Pascal Reynier, Marie Wislez, CHRISTIANE MOUGIN, Patrice VIENS, Helene Blons, Isabelle Borget, Jean-Pierre PIGNON, Denis MORO-SIBILOT, Ivan Bieche, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de compétences pour les maladies pulmonaires rares, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), CHU Strasbourg, Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Hôpital Foch [Suresnes], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), and Université de Lille-UNICANCER

Subjects
Male, Oncology, Lung Neoplasms, Cost effectiveness, Cost-Benefit Analysis, Medical Oncology, MESH: ErbB Receptors, 0302 clinical medicine, Quality of life, Carcinoma, Non-Small-Cell Lung, MESH: Erlotinib Hydrochloride, MESH: Protein Kinase Inhibitors, 030212 general & internal medicine, Epidermal growth factor receptor, 10. No inequality, Erlotinib Hydrochloride, MESH: Medical Oncology, MESH: Aged, MESH: Middle Aged, biology, Middle Aged, Markov Chains, 3. Good health, ErbB Receptors, MESH: Quinazolines, Docetaxel, 030220 oncology & carcinogenesis, Adenocarcinoma, Female, Erlotinib, medicine.drug, Pulmonary and Respiratory Medicine, medicine.medical_specialty, MESH: Mutation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sensitivity and Specificity, 03 medical and health sciences, MESH: Markov Chains, Internal medicine, Carcinoma, medicine, Humans, Protein Kinase Inhibitors, neoplasms, Aged, MESH: Humans, business.industry, MESH: Quality of Life, medicine.disease, MESH: Male, MESH: Sensitivity and Specificity, MESH: Lung Neoplasms, respiratory tract diseases, Surgery, Mutation, Quality of Life, Quinazolines, biology.protein, business, MESH: Female, MESH: Carcinoma, Non-Small-Cell Lung, MESH: Cost-Benefit Analysis
Abstract

International audience; Several clinical and biological parameters are known to influence the efficacy of second-line erlotinib therapy for nonsmall cell lung cancer (NSCLC), but their medico-economic impact has not been evaluated. The objective of this study was to compare the incremental cost-effectiveness ratios of strategies for second-line erlotinib initiation in NSCLC: clinically guided initiation (nonsmoking females with adenocarcinoma received erlotinib; all other patients received docetaxel) and biologically guided selection (patients with epidermal growth factor receptor (EGFR) mutation received erlotinib; patients with wild-type EGFR or unknown status received docetaxel), compared with initiation with no patient selection (strategy reference). A Markov model was constructed. Outcomes (overall and progression-free survival), transition probabilities and direct medical costs (from the French third-party payer's perspective) were prospectively collected for individual patients treated with either erlotinib or docetaxel, from treatment initiation to disease progression. Published data were used to estimate utilities and post-progression costs. Sensitivity analyses were performed. The biologically and clinically guided strategies were both more efficient (incremental quality-adjusted life-yrs equal to 0.080 and 0.081, respectively) and less expensive (cost decrease equal to €5,020 and €5,815, respectively) than the no-selection strategy, and the biologically guided strategy was slightly less expensive than the clinically guided strategy. Sensitivity analyses confirmed the robustness of the results. The cost-effectiveness of second-line NSCLC treatment is improved when patients are selected on either clinical or biological grounds.

Published
2011
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4. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy

Author

Michel Doffoel, Marine Turek, Isabel Fofana, Olivier Poch, Muhammad N. Zahid, Patrick Pessaux, Thomas F. Baumert, Fei Xiao, Laetitia Zona, Christopher Davis, Sebastian Gorke, S. Michael Rothenberg, François-Loïc Cosset, Mirjam B. Zeisel, Laurent Brino, Dimitri Lavillette, Cathy Royer, Thomas Pietschmann, Wolfgang Raffelsberger, Benoit Fischer, Jane A. McKeating, Judith Fresquet, Christopher J. Mee, Arvind H. Patel, Joachim Lupberger, Christine Thumann, Baumert, Thomas F., Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hepatitis C Research Group, Division of Immunity and Infection-University of Birmingham [Birmingham], Department of Medicine II, University of Freiburg [Freiburg], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Massachusetts General Hospital Cancer Center, Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Division of Experimental Virology, Centre for Experimental and Clinical Infection Research (TWINCORE), Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH)-Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH), MRC Virology Unit, University of Glasgow, Service d'Hépato-gastroentérologie, Hôpitaux Universitaires de Strasbourg-Nouvel Hôpital Civil, ERC-2008-AdG-233130-HEPCENT, INTERREG-IV-Rhin Supérieur-FEDER-Hepato-Regio-Net 2009, ANR-05-CEXC-008, ANRS 2008/354, Région Alsace, INCa, NIH, MRC and the Wellcome Trust., École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
MESH: Virus Internalization, Hepacivirus, MESH: Base Sequence, Ligands, medicine.disease_cause, Receptor tyrosine kinase, Mice, Cell-cell transmission, 0302 clinical medicine, Claudin-1, MESH: RNA, Small Interfering, MESH: Ligands, MESH: Protein Kinase Inhibitors, MESH: Animals, MESH: Hepacivirus, Epidermal growth factor receptor, RNA, Small Interfering, MESH: Antigens, CD, MESH: Receptor, EphA2, 0303 health sciences, Phosphotyrosine kinase, biology, Receptor, EphA2, virus diseases, General Medicine, EPH receptor A2, Hepatitis C, 3. Good health, ErbB Receptors, MESH: Quinazolines, Liver, Host-Pathogen Interactions, RNA Interference, 030211 gastroenterology & hepatology, MESH: Membrane Proteins, Tyrosine kinase, MESH: Antiviral Agents, Hepatitis C virus, MESH: RNA Interference, MESH: Receptor, Epidermal Growth Factor, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Antiviral Agents, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, Tetraspanin 28, Erlotinib Hydrochloride, 03 medical and health sciences, MESH: Antigens, CD81, Antigens, CD, Viral entry, medicine, Animals, Humans, Antiviral, Kinase activity, Protein Kinase Inhibitors, MESH: Mice, 030304 developmental biology, MESH: Hepatitis C, MESH: Humans, Base Sequence, MESH: Host-Pathogen Interactions, Erythropoietin-producing hepatocellular (Eph) receptor, Membrane Proteins, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Virus Internalization, Virology, digestive system diseases, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Cell Line, HCV escape variants, Quinazolines, biology.protein
Abstract

International audience; Hepatitis C virus (HCV) is a major cause of liver disease, but therapeutic options are limited and there are no prevention strategies. Viral entry is the first step of infection and requires the cooperative interaction of several host cell factors. Using a functional RNAi kinase screen, we identified epidermal growth factor receptor and ephrin receptor A2 as host cofactors for HCV entry. Blocking receptor kinase activity by approved inhibitors broadly impaired infection by all major HCV genotypes and viral escape variants in cell culture and in a human liver chimeric mouse model in vivo. The identified receptor tyrosine kinases (RTKs) mediate HCV entry by regulating CD81-claudin-1 co-receptor associations and viral glycoprotein-dependent membrane fusion. These results identify RTKs as previously unknown HCV entry cofactors and show that tyrosine kinase inhibitors have substantial antiviral activity. Inhibition of RTK function may constitute a new approach for prevention and treatment of HCV infection.

Published
2011
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5. Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia

Author

Sophie Rigaudeau, Giovanni Martinelli, Pieter Sonneveld, Alison Goudie, Ellin Berman, Sergio Amadori, Hagop M. Kantarjian, Bob Löwenberg, Norbert Ifrah, Philippe Rousselot, Stefan Faderl, Paul K. Stockman, Elias Jabbour, Petra Muus, Gert J. Ossenkoppele, Mojca Jongen-Lavrencic, Jean-Yves Cahn, Hematology, CCA - Innovative therapy, Univers, Transport, Interfaces, Nanostructures, Atmosphère et environnement, Molécules (UMR 6213) (UTINAM), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Service d'hématologie clinique [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Division of Haematology, European Institute of Oncology [Milan] (ESMO), Department of Biopathology, and Università degli Studi di Roma Tor Vergata [Roma]

Subjects
Myeloid, Male, Clinical Trials and Observations, Pharmacology, Biochemistry, Gastroenterology, Severity of Illness Index, MESH: Dose-Response Relationship, Drug, MESH: Aged, 80 and over, 0302 clinical medicine, Aurora Kinases, Recurrence, hemic and lymphatic diseases, 80 and over, MESH: Protein Kinase Inhibitors, Aurora Kinase B, Stomatitis, MESH: Aged, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, Leukemia, Myeloid leukemia, Hematology, Middle Aged, Protein-Serine-Threonine Kinases, Hematologic Response, Organophosphates, 3. Good health, MESH: Quinazolines, Leukemia, Myeloid, Acute, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Toxicity, Female, Drug, MESH: Leukemia, Myeloid, Acute, medicine.medical_specialty, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Acute, Protein Serine-Threonine Kinases, MESH: Protein-Serine-Threonine Kinases, Dose-Response Relationship, 03 medical and health sciences, Pharmacokinetics, Translational research [ONCOL 3], MESH: Severity of Illness Index, Internal medicine, medicine, Humans, Protein Kinase Inhibitors, 030304 developmental biology, Aged, MESH: Humans, Dose-Response Relationship, Drug, business.industry, Quinazolines, Cell Biology, medicine.disease, MESH: Male, MESH: Recurrence, business, MESH: Female, MESH: Organophosphates, Settore MED/15 - Malattie del Sangue, Febrile neutropenia
Abstract

The primary objective of this 2-part phase 1/2 study was to determine the maximum-tolerated dose (MTD) of the potent and selective Aurora B kinase inhibitor barasertib (AZD1152) in patients with newly diagnosed or relapsed acute myeloid leukemia (AML). Part A determined the MTD of barasertib administered as a continuous 7-day infusion every 21 days. In part B, the efficacy of barasertib was evaluated at the MTD. In part A, 32 patients were treated with barasertib 50 mg (n = 3), 100 mg (n = 3), 200 mg (n = 3), 400 mg (n = 4), 800 mg (n = 7), 1200 mg (n = 6), and 1600 mg (n = 6). Dose-limiting toxicities (stomatitis/mucosal inflammation events) were reported in the 800 mg (n = 1), 1200 mg (n = 1), and 1600 mg (n = 2) groups. The MTD was defined as 1200 mg. In part B, 32 patients received barasertib 1200 mg. In each part of the study, 8 of 32 patients had a hematologic response according to Cheson AML criteria. The most commonly reported grade ≥ 3 events were febrile neutropenia (n = 24) and stomatitis/mucosal inflammation (n = 16). We concluded that the MTD of barasertib is 1200 mg in patients with relapsed or newly diagnosed AML. Toxicity was manageable and barasertib treatment resulted in an overall hematologic response rate of 25%. This study is registered at www.ClinicalTrials.gov as NCT00497991.

Published
2011
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6. Economics of Treatments for Non-Small Cell Lung Cancer

Author

Christos Chouaid, Alain Vergnenegre, Kukovi Atsou, Gilles Hejblum, Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pathologie respiratoire et allergologie [CHU Limoges], CHU Limoges, C Chouaid, K Atsou, G Hejblum, SCHILLER A, Pôle de Pharmacie - Santé Publique - Information médicale [Saint-Antoine], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Oncology, MESH: Combined Modality Therapy, Lung Neoplasms, Cost effectiveness, Cost-Benefit Analysis, MESH: Taxoids, Docetaxel, 0302 clinical medicine, Glutamates, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, Medicine, 030212 general & internal medicine, health care economics and organizations, Health Policy, Combined Modality Therapy, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, MESH: Quinazolines, Pemetrexed, 030220 oncology & carcinogenesis, Taxoids, Erlotinib, medicine.drug, medicine.medical_specialty, Guanine, Erlotinib Hydrochloride, 03 medical and health sciences, MESH: Glutamates, Internal medicine, Humans, Lung cancer, MESH: Guanine, Pharmacology, MESH: Humans, Performance status, business.industry, Public Health, Environmental and Occupational Health, Cancer, medicine.disease, MESH: Lung Neoplasms, respiratory tract diseases, Surgery, Localized disease, Quinazolines, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Carcinoma, Non-Small-Cell Lung, MESH: Cost-Benefit Analysis
Abstract

International audience; The purpose of this article is to review the economics of treatments for non-small cell lung cancer (NSCLC). We systematically analysed the cost effectiveness of treatments for the different stages of NSCLC, with particular emphasis on more recently approved agents. Numerous economic analyses in NSCLC have been conducted, with a variety of methods and in a number of countries. In patients with localized disease, adjuvant chemotherapy appears to have greater cost effectiveness than observation; however, there are few published data. In locally advanced disease, combined modalities (chemotherapy, surgery and/or radiotherapy) are probably cost effective, but high-quality economic analyses are lacking. In advanced NSCLC, third-generation chemotherapies used in the first-line setting can be administered with acceptable incremental cost effectiveness. In the second-line setting, new agents (docetaxel, pemetrexed and erlotinib) have acceptable cost effectiveness. The lack of cost-utility analyses for elderly patients and patients with a poor prognosis rules out firm conclusions. This review suggests that most therapies for NSCLC are cost effective when the patient has a good performance status, with an incremental cost-effectiveness ratio under USD 50,000 per life-year gained in the majority of cases.

Published
2009
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7. Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans

Author

Santiago Ferrer, María Santos Martínez, Laura M. Sanz, Sergio Wittlin, Michael J. Delves, Joachim Caron, Nicholas A. Malmquist, Didier Menard, Matthew J. Fuchter, François Nosten, Robert E. Sinden, Artur Scherf, Patty Chen, Francisco-Javier Gamo, María Belén Jiménez-Díaz, Sandeep Sundriyal, Rossarin Suwanarusk, Laurent Rénia, Sandra Duffy, Iñigo Angulo-Barturen, Andrea Ruecker, Benoit Witkowski, Vicky M. Avery, Biologie des Interactions Hôte-Parasite, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry [Imperial College London], Imperial College London, Laboratoire d'épidémiologie moléculaire, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], Diseases of the Developing World [Tres Cantos, Madrid] (DDW), Tres Cantos Open Lab Foundation [London, UK] (TCOLF)-GlaxoSmithKline [Headquarters, London, UK] (GSK), Swiss Tropical and Public Health Institute [Basel], University of Basel (Unibas), Eskitis Institute for Drug Discovery, Griffith University [Brisbane], S.S. acknowledges the European Commission for a Marie Curie International Incoming Fellowship (agreement no. 299857). L.R. was supported by funding from the Singapore Immunology Network (SIgN) and the Horizontal Programme on Infectious Diseases under the Agency for Science, Technology and Research (A*STAR, Singapore). The Shoklo Malaria Research Unit is part of the Mahidol Oxford University Research Unit, supported by the Wellcome Trust of Great Britain. V.M.A. acknowledges support from the Australian Research Council (LP120200557). A.S. acknowledges support from the European Research Council., We thank Xavier Ding and Brice Campo of the Medicines for Malaria Venture for helpful discussions and aid in coordinating some of the collaborative efforts. We thank Jolanda Kamber for assistance in performing the P. berghei in vivo assay and Christoph Siethoff (Swiss BioQuant) for the determination of compound levels in P. berghei-infected mice. We are also grateful to the Therapeutic Efficacy, Pharmacology, and Laboratory Animal Science groups at GSK Tres Cantos Medicines Development Campus for assistance. We thank L. D. Shultz and The Jackson Laboratory for providing access to nonobese diabetic SCID IL-2Rγcnull mice through their collaboration with GSK Tres Cantos Medicines Development Campus. We are indebted to Susan A. Charman of Monash University for critically reviewing the manuscript., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Oxford-University of Oxford, and University of Oxford-Mahidol University [Bangkok]

Subjects
MESH: Histone Methyltransferases, Plasmodium berghei, Plasmodium vivax, Mice, SCID, Pharmacology, Mice, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Pharmacology (medical), MESH: Animals, Artemisinin, Malaria, Falciparum, MESH: Mice, SCID, MESH: Plasmodium falciparum, biology, MESH: Malaria, Falciparum, Azepines, Hep G2 Cells, 3. Good health, MESH: Quinazolines, Infectious Diseases, Histone Methyltransferases, Female, medicine.drug, Plasmodium falciparum, MESH: Malaria, MESH: Hep G2 Cells, Antimalarials, In vivo, parasitic diseases, medicine, Gametocyte, Animals, Humans, MESH: Plasmodium berghei, Experimental Therapeutics, MESH: Mice, MESH: Humans, MESH: Histone-Lysine N-Methyltransferase, Histone-Lysine N-Methyltransferase, biology.organism_classification, Virology, MESH: Antimalarials, Malaria, Multiple drug resistance, Quinazolines, MESH: Azepines, MESH: Female, Ex vivo
Abstract

Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising in vitro parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for in vitro and in vivo efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent in vitro activity, with 50% inhibitory concentrations (IC 50 s) of Plasmodium falciparum isolates. Activities against ex vivo clinical isolates of both P. falciparum and Plasmodium vivax were similar, with potencies of 300 to 400 nM. Sexual-stage gametocyte inhibition occurs at micromolar levels; however, mature gametocyte progression to gamete formation is inhibited at submicromolar concentrations. Parasite reduction ratio analysis confirms a high asexual-stage rate of killing. Both compounds examined displayed oral efficacy in in vivo mouse models of Plasmodium berghei and P. falciparum infection. The discovery of a rapid and broadly acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria-causing species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.

Published
2015
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8. Properly Substituted Analogues of BIX-01294 Lose Inhibition of G9a Histone Methyltransferase and Gain Selective Anti-DNA Methyltransferase 3A Activity

Author

Manfred Jung, Dante Rotili, Domenico Tarantino, Biagina Marrocco, Christina Gros, Veronique Masson, Valerie Poughon, Frederic Ausseil, Yanqi Chang, Donatella Labella, Sandro Cosconati, Salvatore Di Maro, Michael Schnekenburger, Cindy Grandjenette, Celine Bouvy, Marc Diederich, Xiaodong Cheng, Paola B. Arimondo, Antonello Mai, NOVELLINO, ETTORE, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-PIERRE FABRE, Emory University School of Medicine, Emory University [Atlanta, GA], Seconda Università degli studi di Napoli, Università degli studi di Napoli Federico II, Laboratoire de Biologie Moléculaire et Cellulaire du Cancer [Luxembourg] (LBMCC), Hôpital Kirchberg [Luxembourg], Seoul National University [Seoul] (SNU), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), This work was supported by PRIN 2009PX2T2E, FIRB RBFR10ZJQT, Progetto Ateneo Sapienza 2012, Progetto IIT-Sapienza, FP7 Projects BLUEPRINT/282510 and COST/TD0905, the U.S. National Institutes of Health (5R01GM049245-20 and 1DP3DK094346-01), the FNRS Télévie Luxembourg grant 7.4612.12.F, the «Recherche Cancer et Sang foundation, and the «Recherches Scientifiques Luxembourg and «Een Häerz fir Kriibskrank Kanner associations. X. Cheng is a Georgia Research Alliance Eminent Scholar. P.B. Arimondo is supported by ATIP CNRS and Région Midi-Pyrenées (Equipe d’Excellence and FEDER). M. Schnekenburger is supported by a 'Waxweiler grant for cancer prevention research' from the Action Lions 'Vaincre le Cancer'. C. Gros is supported by Fondation de la Recherche Médicale. C. Grandjenette is a recipient of a postdoctoral grant from FNRS Télévie Luxembourg. M. Diederich is supported by the NRF by the MEST of Korea for Tumor Microenvironment GCRC 2012-0001184 grant., European Project: 282510,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,BLUEPRINT(2011), Rotili, D, Tarantino, D, Marrocco, B, Gros, C, Masson, V, Poughon, V, Ausseil, F, Chang, Y, Labella, D, Cosconati, Sandro, DI MARO, Salvatore, Novellino, E, Schnekenburger, M, Grandjenette, C, Bouvy, C, Diederich, M, Cheng, X, Arimondo, Pb, Mai, A., Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Seconda Università degli Studi di Napoli = Second University of Naples, University of Naples Federico II = Università degli studi di Napoli Federico II, Manfred, Jung, Dante, Rotili, Domenico, Tarantino, Biagina, Marrocco, Christina, Gro, Veronique, Masson, Valerie, Poughon, Frederic, Ausseil, Yanqi, Chang, Donatella, Labella, Sandro, Cosconati, Salvatore Di, Maro, Novellino, Ettore, Michael, Schnekenburger, Cindy, Grandjenette, Celine, Bouvy, Marc, Diederich, Xiaodong, Cheng, Paola B., Arimondo, and Antonello, Mai

Subjects
Methyltransferase, Cancer Treatment, lcsh:Medicine, MESH: Catalytic Domain, Biochemistry, DNA Methyltransferase 3A, MESH: Structure-Activity Relationship, Catalytic Domain, Histocompatibility Antigens, Molecular Cell Biology, Medicine and Health Sciences, DNA (Cytosine-5-)-Methyltransferases, Enzyme Inhibitors, lcsh:Science, Multidisciplinary, biology, Cell Death, Chemical Synthesis, Histone Modification, Heterocycle Structures, Methylation, Azepines, 3. Good health, Molecular Docking Simulation, Chemistry, MESH: Quinazolines, Histone, Oncology, MESH: Cell Survival, Cell Processes, MESH: Enzyme Inhibitors, Histone methyltransferase, DNA methylation, Physical Sciences, Epigenetics, DNA modification, Research Article, MESH: DNA (Cytosine-5-)-Methyltransferases, MESH: Cell Line, Tumor, Cell Survival, Research and Analysis Methods, DNA methyltransferase, Cell Growth, Epigenetic Therapy, Histone H3, Structure-Activity Relationship, Cell Line, Tumor, MESH: Cell Proliferation, Genetics, MESH: Molecular Docking Simulation, Humans, [CHIM]Chemical Sciences, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cell Proliferation, MESH: Humans, Biology and life sciences, lcsh:R, Organic Chemistry, MESH: Histocompatibility Antigens, MESH: Histone-Lysine N-Methyltransferase, Histone-Lysine N-Methyltransferase, DNA, Cell Biology, Molecular biology, biology.protein, DNMT1, Quinazolines, lcsh:Q, Medicinal Chemistry, MESH: Azepines
Abstract

International audience; Chemical manipulations performed on the histone H3 lysine 9 methyltransferases (G9a/GLP) inhibitor BIX-01294 afforded novel desmethoxyquinazolines able to inhibit the DNA methyltransferase DNMT3A at low micromolar levels without any significant inhibition of DNMT1 and G9a. In KG-1 cells such compounds, when tested at sub-toxic doses, induced the luciferase re-expression in a stable construct controlled by a cytomegalovirus (CMV) promoter silenced by methylation (CMV-luc assay). Finally, in human lymphoma U-937 and RAJI cells, the N-(1-benzylpiperidin-4-yl)-2-(4-phenylpiperazin-1-yl)quinazolin-4-amine induced the highest proliferation arrest and cell death induction starting from 10 µM, in agreement with its DNMT3A inhibitory potency.

Published
2014
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9. Insulin-like growth factor-1 receptor inhibition overcomes gefitinib resistance in mucinous lung adenocarcinoma

Author

Elisabeth Brambilla, Sandrine Dufort, Nathalie Rabbe, Martine Antoine, Denis Moro-Sibilot, Florence de Fraipont, C. Tenaud, Amandine Hurbin, Marie Wislez, Benoit Busser, Jacques Cadranel, Jean-Luc Coll, INSERM U823, équipe 5 (cibles diagnostiques ou thérapeutiques et vectorisation de drogues dans le cancer du poumon), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions cellulaires tumorales et leur environnement et réponse aux agents anti-cancéreux, Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Biochimie des Cancers et Biothérapies, CHU Grenoble-Hôpital Michallon-Hôpital Michallon, Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Biochimie des Cancers et Biothérapies, Pôle Médecine Aigüe Communautaire Pneumologie, CHU Grenoble, INSERM U823, équipe 2 (Bases Moléculaires de la Progression des Cancers du Poumon), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon-Hôpital Michallon-Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique-Intergroupe Francophone de Cancérologie thoracique, This work was supported by grants from 'La Ligue contre le Cancer, comité de l'Isère', 'projet libre INCa', 'Programme National d'Excellence Spécialisée 2005-2007 and Pharmacogenoscan PHRC 2003., and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Oncology, MESH: Neoplasm Proteins, MESH: Adenocarcinoma, Mucinous, medicine.medical_treatment, medicine.disease_cause, Insulin-like growth factor, 0302 clinical medicine, MESH: Receptor, IGF Type 1, MESH: Aged, 80 and over, Epidermal growth factor, IGF1R, Neoplasm, MESH: Treatment Outcome, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: Drug Resistance, Neoplasm, 3. Good health, MESH: Quinazolines, 030220 oncology & carcinogenesis, Adenocarcinoma, KRAS, amphiregulin, medicine.drug, medicine.medical_specialty, MESH: Mutation, mucinous, MESH: Glycoproteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Receptor, Epidermal Growth Factor, Pathology and Forensic Medicine, 03 medical and health sciences, Gefitinib, Amphiregulin, Internal medicine, EGFR-TKI, medicine, MESH: Tumor Cells, Cultured, MESH: Intercellular Signaling Peptides and Proteins, 030304 developmental biology, Insulin-like growth factor 1 receptor, MESH: Humans, business.industry, MESH: MAP Kinase Signaling System, MESH: Adenocarcinoma, MESH: Adult, medicine.disease, lung adenocarcinoma, MESH: Male, respiratory tract diseases, MESH: Lung Neoplasms, MESH: Tumor Markers, Biological, MESH: Antineoplastic Agents, business, MESH: Female, MESH: DNA-Binding Proteins
Abstract

International audience; The appropriate selection of patients is a major challenge in the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Prospective trials in adenocarcinoma demonstrated that the mucinous subtype presents a poorer outcome under EGFR-TKI treatment than the non-mucinous subtype. Our aim was to determine the molecular characteristics associated with resistance to EGFR-TKIs in mucinous and non-mucinous adenocarcinoma. Eighty adenocarcinoma samples, including 34 tumours from patients treated with gefitinib in a phase II clinical trial (IFCT0401), were classified as mucinous (n = 32) or non-mucinous (n = 48) adenocarcinoma. We demonstrated that four biological markers were differentially expressed between the two subtypes: mucinous tumours that overexpressed IGF1R (p < 0.0001) and amphiregulin (p = 0.004) with a tendency for more frequent KRAS mutations, in contrast to non-mucinous tumours that overexpressed EGFR (p < 0.0001) and TTF-1 (p < 0.0001) with more frequent EGFR mutations (p = 0.037). Higher IGF1R (p = 0.02) and lower TTF-1 (p = 0.02) expression was associated with disease progression under gefitinib treatment. We observed in vitro cross-talk between EGFR and IGF1R signalling pathways in gefitinib-resistant H358 mucinous cells. Anti-amphiregulin siRNAs and anti-IGF1R treatments sensitized the H358 cells to gefitinib-induced apoptosis with additive effects, suggesting that these treatments could overcome the resistance of mucinous tumours to EGFR-TKIs, including those with KRAS mutation. Our results highlighted that mucinous and non-mucinous adenocarcinoma subtypes are different entities with different therapeutic responses to EGFR-TKIs. These data will foster the development of therapeutic strategies for treating adenocarcinoma with mucinous component.

Published
2011
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10. Kinase inhibitors in the treatment of chronic hepatitis C virus

Author

Edouard Bardou-Jacquet, Dominique Guyader, R. Lorho, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service des maladies du foie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Microenvironnement et remodelage, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Service des maladies du foie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes]-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service des maladies du foie [CHU Rennes], Centre Hospitalier Universitaire [Rennes], Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Service des maladies du foie [CHU Rennes], and Centre Hospitalier Universitaire [Rennes]-Centre Hospitalier Universitaire [Rennes]

Subjects
MAPK/ERK pathway, Sorafenib, MESH: Antiviral Agents, MESH: Fatal Outcome, MESH: Liver Transplantation, 03 medical and health sciences, 0302 clinical medicine, medicine, MESH: Protein Kinase Inhibitors, Epidermal growth factor receptor, Protein kinase A, NS5A, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, MESH: Humans, biology, Cyclin-dependent kinase 4, Cyclin-dependent kinase 2, Gastroenterology, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Follow-Up Studies, MESH: Male, 3. Good health, MESH: Hepatitis C, Chronic, MESH: Quinazolines, Cancer research, biology.protein, 030211 gastroenterology & hepatology, Erlotinib, medicine.drug
Abstract

We read with great interest the publication in Gut by Himmelsbach et al 1 in which they assessed whether the modulation of c-Raf by sorafenib affects hepatitis C virus (HCV) replication using the in vitro replicon system. The authors showed that sorafenib blocks HCV replication in vitro, by decreasing c-Raf phosphorylation and by affecting the post-translational processing of NS5A, which is required for the replication of the virus. We would like to report here a clinical observation that could suggest the clinical potential interest of kinase pathway inhibitors as a therapeutic option in chronic hepatitis C. Erlotinib is a highly selective kinase inhibitor targeting epidermal growth factor receptor (EGFR), the signalling pathway of which includes the Ras/Raf/mitogen-activated protein kinase (MEK)/extracellular-related-signal kinase (ERK) pathway. Erlotinib has been approved in non-small cell lung …

Published
2011
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11. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer

Author

Cristina Oliva, M. John Kennedy, Gilles Romieu, Xavier Pivot, Michael F. Press, J. Maltzman, S. Stein, Stephen S. Johnston, L. O'Rourke, Henry L. Gomez, Mikhail Lichinitser, A. Florance, John Pippen, Alexey Manikhas, Saeed Sadeghi, Véronique Diéras, Mark D. Pegram, Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Saas, Philippe, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])

Subjects
Oncology, MESH: Carcinoma, Cancer Research, Receptor, ErbB-2, Kaplan-Meier Estimate, MESH: Risk Assessment, MESH: Dose-Response Relationship, Drug, MESH: Proportional Hazards Models, 0302 clinical medicine, MESH: Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, MESH: Double-Blind Method, MESH: Kaplan-Meiers Estimate, skin and connective tissue diseases, MESH: Treatment Outcome, Aged, 80 and over, MESH: Aged, 0303 health sciences, education.field_of_study, MESH: Middle Aged, Letrozole, MESH: Maximum Tolerated Dose, MESH: Neoplasm Staging, Middle Aged, MESH: Antineoplastic Agents, Hormonal, Prognosis, Metastatic breast cancer, MESH: Nitriles, 3. Good health, Postmenopause, MESH: Quinazolines, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, Receptors, Estrogen, MESH: Receptor, erbB-2, 030220 oncology & carcinogenesis, MESH: Survival Analysis, MESH: Receptors, Estrogen, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Receptors, Progesterone, MESH: Postmenopause, medicine.drug, Adult, MESH: Receptors, Progesterone, medicine.medical_specialty, Antineoplastic Agents, Hormonal, Maximum Tolerated Dose, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.drug_class, Population, Breast Neoplasms, MESH: Drug Administration Schedule, Lapatinib, Risk Assessment, Disease-Free Survival, Drug Administration Schedule, MESH: Prognosis, 03 medical and health sciences, Breast cancer, Double-Blind Method, Internal medicine, Nitriles, medicine, Biomarkers, Tumor, Humans, Neoplasm Invasiveness, education, 030304 developmental biology, Aged, Neoplasm Staging, Proportional Hazards Models, Aromatase inhibitor, MESH: Humans, Dose-Response Relationship, Drug, business.industry, Carcinoma, MESH: Adult, MESH: Neoplasm Invasiveness, Triazoles, Antiestrogen, medicine.disease, Survival Analysis, Endocrinology, MESH: Triazoles, MESH: Tumor Markers, Biological, MESH: Disease-Free Survival, Quinazolines, business, MESH: Female, Tamoxifen, MESH: Breast Neoplasms
Abstract

PurposeCross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) –positive metastatic breast cancer (MBC).Patients and MethodsPostmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population.ResultsIn HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease ≥ 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable.ConclusionThis trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.

Published
2009
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12. Lessons from Tarceva in pancreatic cancer: where are we now, and how should future trials be designed in pancreatic cancer?

Author

Julien Taieb, Pierre Laurent-Puig, Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Bases moléculaires de la réponse aux xénobiotiques ( U775 (IFR95) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Hôpital Européen Georges Pompidou [APHP] ( HEGP )

Subjects
Cancer Research, MESH: Clinical Trials as Topic, medicine.medical_treatment, MESH: Receptor, Epidermal Growth Factor, Targeted therapy, 03 medical and health sciences, Erlotinib Hydrochloride, 0302 clinical medicine, MESH : Quinazolines, MESH : Receptor, Epidermal Growth Factor, Pancreatic cancer, medicine, MESH: Protein Kinase Inhibitors, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein Kinase Inhibitors, 030304 developmental biology, 0303 health sciences, Clinical Trials as Topic, MESH: Humans, business.industry, MESH : Humans, MESH: Research Design, MESH : Protein Kinase Inhibitors, MESH : Research Design, medicine.disease, 3. Good health, MESH : Clinical Trials as Topic, ErbB Receptors, Pancreatic Neoplasms, MESH: Quinazolines, Oncology, Research Design, 030220 oncology & carcinogenesis, Immunology, Cancer research, Quinazolines, Pancreatic carcinogenesis, MESH: Pancreatic Neoplasms, business, MESH : Pancreatic Neoplasms
Abstract

PURPOSE OF REVIEW: The recent advances in the use of targeted therapy in pancreatic cancer are based on the knowledge of genetic alterations that occur during pancreatic carcinogenesis. We describe the repository of frequent alterations targeting tumour suppressor genes and oncogenes. We focus our attention on the epidermal growth factor receptor signalling pathway, which can be activated through different alterations and seems to play a central role in the cell transformation. Multiple targeted drugs have been developed against different partners of this network trying to improve the treatment of pancreatic cancer patients. RECENT FINDINGS: Tarceva has obtained approval in the USA and Europe for metastatic pancreatic cancer with a modest increase of median survival and a 6% increase in 1-year survival rates, suggesting that only a small fraction of patients truly benefit from it. The comparison with lung and colon cancer suggests that Kras mutations could be a predictive marker of resistance. Other promising drugs targeting different partners of the epidermal growth factor receptor signalling pathway could play a synergistic role with Tarceva as inhibitors of mTOR, mitogen-activated protein kinase kinase 1, and nuclear factor-kappaB or can directly turn down Ras. SUMMARY: The biology of the epidermal growth factor receptor, mitogen-activated protein kinase, PI3K/mTOR network suggests that a combination of drugs targeting simultaneously different partners should improve survival.

Published
2008
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13. Antifolate screening using yeast expressing Plasmodium vivax dihydrofolate reductase and in vitro drug susceptibility assay for Plasmodium falciparum

Author

Jeanne Ngogang Yonkeu, Ruth Zelikson, Joseph Allico Djaman, Andre Rosowsky, Liselotte Yimga Djapa, Leonardo K. Basco, André Mazabraud, Monique Bolotin-Fukuhara, Institut de génétique et microbiologie [Orsay] (IGM), and Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Plasmodium vivax, Mutant, Drug resistance, MESH: Tetrahydrofolate Dehydrogenase, yeast, MESH: Parasitic Sensitivity Tests, chemistry.chemical_compound, 0302 clinical medicine, Parasitic Sensitivity Tests, Dihydrofolate reductase, MESH: Animals, MESH: Plasmodium falciparum, MESH: Inhibitory Concentration 50, 0303 health sciences, biology, antifolate drugs, MESH: Saccharomyces cerevisiae, 3. Good health, MESH: Plasmodium vivax, MESH: Quinazolines, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Antifolate, MESH: Mutation, Plasmodium falciparum, 030231 tropical medicine, Saccharomyces cerevisiae, malaria, Plasmodium falciparum in vitro culture, Inhibitory Concentration 50, 03 medical and health sciences, parasitic diseases, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Gene, 030304 developmental biology, MESH: Folic Acid Antagonists, drug resistance, biology.organism_classification, Virology, Tetrahydrofolate Dehydrogenase, chemistry, Mutation, Quinazolines, biology.protein, Folic Acid Antagonists, Parasitology
Abstract

The presence of homologous point mutations in the dhfr gene in Plasmodium vivax and Plasmodium falciparum is associated with resistance to antifolate drugs. The spread of antifolate resistance encouraged research for novel antifolate drugs active against both wild-type and dhfr-mutant strains of malaria parasites. Because P. vivax cannot be easily maintained in culture, we transformed a Saccharomyces cerevisiae DHFR-deleted mutant to express wild-type P. vivax dhfr gene and its mutant forms. Twenty-five dicyclic and tricyclic 2,4-diaminopyrimidine derivatives were screened. Six quinazoline compounds showed selective inhibition of yeast transformants expressing P. vivax dhfr genes. The 50% inhibitory concentration (IC50) of these six compounds was determined against field isolates of P. falciparum. Our results suggest that a close relationship between the yeast assay based on expression of P. vivax dhfr genes and the in vitro test using P. falciparum parasites in culture is a promising initial step for drug screening.

Published
2007
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14. Economic impact of gefitinib for refractory non-small-cell lung cancer: a Markov model-based analysis

Author

Maurice Pérol, Gilles Robinet, Alain Vergnenegre, Isabelle Monnet, Pierre Fournel, Christos Chouaid, Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Service de Pneumologie 93, Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Département d'Oncologie médicale, Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de Pathologie respiratoire et allergologie [CHU Limoges], CHU Limoges, Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), and Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)

Subjects
Male, Oncology, Lung Neoplasms, Indirect costs, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, MESH: Drug Costs, 030212 general & internal medicine, health care economics and organizations, MESH: Aged, MESH: Middle Aged, Gefitinib, General Medicine, Middle Aged, Markov Chains, 3. Good health, MESH: Quinazolines, 030220 oncology & carcinogenesis, MESH: Survival Analysis, Cohort, Costs and Cost Analysis, Female, Non small cell, medicine.drug, medicine.medical_specialty, Antineoplastic Agents, Markov model, MESH: Costs and Cost Analysis, Drug Costs, 03 medical and health sciences, Refractory, MESH: Markov Chains, Internal medicine, medicine, Humans, Target therapy, Lung cancer, neoplasms, Aged, MESH: Humans, business.industry, medicine.disease, Survival Analysis, MESH: Male, Surgery, respiratory tract diseases, MESH: Lung Neoplasms, Quinazolines, MESH: Antineoplastic Agents, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, MESH: Carcinoma, Non-Small-Cell Lung
Abstract

International audience; UNLABELLED: Few data are available on the economics of target therapy or refractory non-small-cell lung cancer (NSCLC). OBJECTIVE: To determine the mean global management costs (MC) per patient treated with gefitinib for NSCLC, and the costs of the different management phases. METHOD: A Markov approach was used to model treatment costs in a cohort of 106 patients treated with gefitinib as part of a compassionate-use program (third-line treatment) in six public-sector teaching hospitals. The economic analysis adopted the health care payer's perspective, and only direct costs were taken into account. RESULTS: The mean duration of gefitinib treatment was 4.6 +/- 5.8 months (1-29 months); median survival was 4 months, 1-year and 2-year survival rates were 12.3% and 4.7%, respectively. The mean total management cost was 39,979 euros +/- 20,279. The model showed that first- and second-line treatments accounted for respectively 29.5% and 44.1% of this cost, while gefitinib periods represented 10.7%, periods of remission 1.25%, and terminal care 14.5%. A sensitivity analysis showed that the price of gefitinib had little influence on the total cost. CONCLUSION: The cost of third-line gefitinib therapy for NSCLC appears acceptable from the healthcare payer's perspective, but this needs to be confirmed in dedicated cost-effectiveness studies.

Published
2007
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15. Identification of nonpeptide CCR5 receptor agonists by structure-based virtual screening

Author

Jean-Yves Springael, Didier Rognan, Marc Parmentier, Jean-Luc Galzi, Esther Kellenberger, Muriel Hachet-Haas, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Faculteit Toegepaste Economische Wetenschappen (TEW), University of Antwerp (UA), Agence Universitaire de la Francophonie (AUF), Récepteurs et protéines membranaires (RPM), Centre National de la Recherche Scientifique (CNRS), Pharmacochimie de la communication cellulaire (PCC), Instiitut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université de Bruxelles, Université libre de Bruxelles (ULB), Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)

Subjects
Models, Molecular, Pyrrolidines, Chemokine receptor CCR5, MESH: Sequence Homology, Amino Acid, MESH: Piperazines, Quantitative Structure-Activity Relationship, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Amino Acid Sequence, MESH: Receptors, CCR5, 01 natural sciences, Piperazines, MESH: Protein Structure, Tertiary, Piperidines, Drug Discovery, Receptor, 0303 health sciences, MESH: Quantitative Structure-Activity Relationship, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Molecular Structure, Chemistry, virus diseases, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, Pyridazines, MESH: Quinazolines, MESH: Piperidines, CCR5 Receptor Antagonists, Molecular Medicine, Pharmacophore, [CHIM.CHEM]Chemical Sciences/Cheminformatics, MESH: Models, Molecular, Agonist, Receptors, CCR5, Stereochemistry, medicine.drug_class, In silico, MESH: Molecular Structure, Molecular Sequence Data, CCR5 receptor antagonist, Computational biology, 03 medical and health sciences, MESH: Pyridazines, medicine, Amino Acid Sequence, 030304 developmental biology, Virtual screening, MESH: Molecular Sequence Data, MESH: Pyrrolidines, Sequence Homology, Amino Acid, Triazoles, 0104 chemical sciences, Protein Structure, Tertiary, 010404 medicinal & biomolecular chemistry, MESH: Triazoles, Docking (molecular), biology.protein, Quinazolines
Abstract

International audience; A three-dimensional model of the chemokine receptor CCR5 has been built to fulfill structural peculiarities of its alpha-helix bundle and to distinguish known CCR5 antagonists from randomly chosen drug-like decoys. In silico screening of a library of 1.6 million commercially available compounds against the CCR5 model by sequential filters (drug-likeness, 2-D pharmacophore, 3-D docking, scaffold clustering) yielded a hit list of 59 compounds, out of which 10 exhibited a detectable binding affinity to the CCR5 receptor. Unexpectedly, most binders tested in a functional assay were shown to be agonists of the CCR5 receptor. A follow-up database query based on similarity to the most potent binders identified three new CCR5 agonists. Despite a moderate affinity of all nonpeptide ligands for the CCR5 receptor, one of the agonists was shown to promote efficient receptor internalization, which is a process therapeutically favorable for protection against HIV-1 infection.

Published
2007
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16. Synthesis of the PPARbeta/delta-selective agonist GW501516 and C4-thiazole-substituted analogs

Author

Hinrich Gronemeyer, Beatriz Iglesias, Claudine Gaudon, Pierre Germain, Angel R. de Lera, Raquel Pereira, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Time Factors, Transcription, Genetic, Chemistry, Pharmaceutical, Clinical Biochemistry, Pharmaceutical Science, MESH: Drug Design, Ligands, 01 natural sciences, Biochemistry, Chemical synthesis, chemistry.chemical_compound, Suzuki reaction, Genes, Reporter, Drug Discovery, Hydroxybenzoates, MESH: Ligands, PPAR delta, Promoter Regions, Genetic, chemistry.chemical_classification, MESH: Models, Chemical, Lipids, 3. Good health, Globins, MESH: Promoter Regions (Genetics), MESH: Quinazolines, Genetic Techniques, Molecular Medicine, MESH: Palladium, Palladium, Agonist, Transcriptional Activation, MESH: PPAR-beta, medicine.drug_class, Stereochemistry, Carboxylic acid, MESH: Thiazoles, Ether, MESH: Hydroxybenzoic Acids, 010402 general chemistry, Catalysis, GW501516, Cell Line, MESH: Chemistry, Pharmaceutical, mental disorders, medicine, MESH: Globins, Humans, MESH: PPAR delta, Thiazole, Molecular Biology, PPAR-beta, MESH: Humans, 010405 organic chemistry, MESH: Transcription, Genetic, Organic Chemistry, MESH: Time Factors, MESH: Genes, Reporter, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Catalysis, MESH: Lipids, 0104 chemical sciences, Stille reaction, MESH: Cell Line, MESH: Hela Cells, Thiazoles, MESH: Genetic Techniques, chemistry, Models, Chemical, MESH: Trans-Activation (Genetics), Drug Design, Quinazolines, HeLa Cells
Abstract

Sequential, position-selective, Pd-catalyzed cross-coupling reactions of 2,4-dibromo-5-hydroxymethylthiazole provided the scaffold for the synthesis of GW501516, the most potent PPARbeta/delta agonist yet described, and equally selective analogs at the thiazole-C4 position.

Published
2006
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17. Synthesis and evaluation of the antiproliferative activity of novel thiazoloquinazolinone kinases inhibitors

Author

Thierry Besson, Jean-Marie Piot, Olivier Lozach, Laurent Meijer, Mélina Blairvacq, Alexandra Testard, Valérie Thiéry, Laurent Picot, Laurence Murillo, LIttoral ENvironnement et Sociétés (LIENSs), La Rochelle Université (ULR)-Centre National de la Recherche Scientifique (CNRS), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Phophorylation de protéines et Pathologies Humaines (P3H), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), LIttoral ENvironnement et Sociétés - UMRi 7266 (LIENSs), Université de La Rochelle (ULR)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Cell Line, Tumor, MESH: Molecular Structure, Drug Evaluation, Preclinical, MESH: Microwaves, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, Glycogen Synthase Kinase 3, Structure-Activity Relationship, MESH: Structure-Activity Relationship, Cyclin-dependent kinase, GSK-3, Cell Line, Tumor, MESH: Cell Proliferation, Drug Discovery, Structure–activity relationship, Humans, Enzyme Inhibitors, Microwaves, 030304 developmental biology, Cell Proliferation, MESH: Glycogen Synthase Kinase 3, Pharmacology, 0303 health sciences, MESH: Humans, biology, Molecular Structure, 010405 organic chemistry, Kinase, Chemistry, [SDV.BA]Life Sciences [q-bio]/Animal biology, General Medicine, Cyclin-Dependent Kinases, 0104 chemical sciences, 3. Good health, MESH: Quinazolines, MESH: Cyclin-Dependent Kinases, Biochemistry, Cell culture, MESH: Enzyme Inhibitors, biology.protein, Quinazolines, MESH: Drug Evaluation, Preclinical, Lead compound
Abstract

International audience; The microwave-assisted synthesis of a family of 2,8-substituted thiazoloquinazolinones is described. The preliminary evaluation of the antiproliferative activity and the capacity of these molecules to inhibit CDKs and GSK-3 are reported. A lead compound was identified, constituting a scaffold from which more potent inhibitors could be designed.

Published
2005
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18. Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells

Author

Geneviève Fiol, Dirk Hose, Friedrich W. Cremer, Veronique Grau, Jean François Rossi, Bernard Klein, Hartmut Goldschmidt, Marion Moos, Eric Jourdan, Jérôme Moreaux, Karène Mahtouk, Thierry Rème, Michel Jourdan, Marion Baudard, Marc-Steffen Raab, John De Vos, Frei, Monique, Immunopathologie des maladies tumorales et autoimmunes, Université Montpellier 1 (UM1)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Internal Medicine V, Universität Heidelberg [Heidelberg], Service de médecine interne B, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Institut für Humangenetik, and Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)

Subjects
Cancer Research, medicine.medical_treatment, Apoptosis, MESH: Multiple Myeloma, medicine.disease_cause, ErbB Receptors, 0302 clinical medicine, Multiple myeloma, Oligonucleotide Array Sequence Analysis, 0303 health sciences, MESH: Plasma Cells, Reverse Transcriptase Polymerase Chain Reaction, MESH: Bone Marrow Cells, Gefitinib, 3. Good health, MESH: Quinazolines, 030220 oncology & carcinogenesis, Intercellular Signaling Peptides and Proteins, Multiple Myeloma, EGF Family of Proteins, Stromal cell, Plasma Cells, MESH: Glycoproteins, Antineoplastic Agents, Bone Marrow Cells, Biology, Amphiregulin, Article, 03 medical and health sciences, MESH: Gene Expression Profiling, ErbB, MESH: Cell Proliferation, Genetics, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Intercellular Signaling Peptides and Proteins, Molecular Biology, 030304 developmental biology, Cell Proliferation, Glycoproteins, MESH: Humans, Cell growth, Growth factor, Gene Expression Profiling, MESH: Apoptosis, medicine.disease, MESH: Oligonucleotide Array Sequence Analysis, Cancer research, Quinazolines, MESH: Antineoplastic Agents, Carcinogenesis
Abstract

International audience; A hallmark of plasma cells is the expression of syndecan-1, which has major functions in epithelial cells, in particular as the coreceptor of heparin-binding growth factors. We previously found that heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a growth factor for malignant plasma cells. As amphiregulin (AREG) is another heparin-binding factor of the EGF family, we investigated its role in multiple myeloma (MM). Using Affymetrix DNA microarrays, we show here that the AREG gene was expressed by purified primary myeloma cells from 65 patients and that the expression was higher than in normal bone marrow (BM) plasma cells or plasmablastic cells. AREG stimulated IL-6 production and growth of BM stromal cells. Using real-time reverse transcriptase-polymerase chain reaction, we found that MM cells expressed ErbB receptors and that AREG promoted their growth. Furthermore, PD169540 (a pan-ErbB inhibitor) and IRESSA (an ErbB1-specific inhibitor) induced apoptosis of primary myeloma cells from 10/14 and 4/14 patients, respectively, and there was a synergistic effect with dexamethasone. Altogether, our data provide strong evidence that AREG plays an important role in the biology of MM and emphasize the advantages of using ErbB inhibitors, which might target myeloma cells as well as the tumor environment.

Published
2005
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