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11 results on '"Béatrice Josselin"'

1. Synthesis and evaluation of C3 substituted chalcone‐based derivatives of 7‐azaindole as protein kinase inhibitors

Author

Lesetja J. Legoabe, Malikotsi A. Qhobosheane, Richard M. Beteck, Stéphane Bach, Béatrice Josselin, Sandrine Ruchaud, Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), 12902608 - Legoabe, Lesetja Jan, 25159194 - Beteck, Richard Mbi, and 27836576 - Qhobosheane, Malikotsi A.

Subjects
Chalcone, Indoles, Stereochemistry, [SDV]Life Sciences [q-bio], Antineoplastic Agents, Structure-activity relationships, 01 natural sciences, Biochemistry, Protein kinase, Structure-Activity Relationship, chemistry.chemical_compound, Chalcones, CDK9/CyclinT, Cell Line, Tumor, Drug Discovery, Ic50 values, Humans, [CHIM]Chemical Sciences, Potency, Protein kinase A, Protein Kinase Inhibitors, IC50, ComputingMilieux_MISCELLANEOUS, Pharmacology, 010405 organic chemistry, Chemistry, Kinase, Haspin, 7‐Azaindole, Organic Chemistry, Dual inhibitor, 3. Good health, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Drug Design, Molecular Medicine, Cyclin-dependent kinase 9
Abstract

Chalcones are a group of naturally occurring or synthetic compounds which possess a wide range of biological activities. In this paper, a series of twenty-three 7-azaindole-chalcone hybrids (5a-w) were synthesized and evaluated as potential protein kinase inhibitors. Analyses of structure-activity relationships revealed that some of these compounds exhibit significant activity against Haspin kinase, with compounds 5f and 5q exhibiting IC50 values of 0.47 and 0.41 µM, respectively. Furthermore, 5f also inhibits cyclin-dependent kinase 9 (CDK9/CyclinT) in a micromolar potency (IC50 = 2.26 µM). This novel dual-target inhibitor is a promising lead for the development of chemopreventive/chemotherapeutic agents.

Published
2020
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2. Kinase inhibitions in pyrido[4,3-h] and [3,4-g]quinazolines: Synthesis, SAR and molecular modeling studies

Author

Béatrice Josselin, Yannick J. Esvan, Fabrice Anizon, Wael Zeinyeh, Vincent Théry, Blandine Baratte, Lionel Nauton, Stéphane Bach, Pascale Moreau, Sandrine Ruchaud, Francis Giraud, Institut de Chimie de Clermont-Ferrand (ICCF), SIGMA Clermont (SIGMA Clermont)-Institut de Chimie du CNRS (INC)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Plate-forme de criblage d'inhibiteurs de protéines kinases=Kinase Inhibitor Specialized Screening facility (KISSf), Fédération de recherche de Roscoff (FR2424), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Intégrative (LBI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), and Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Molecular model, Pyridines, Stereochemistry, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Pharmaceutical Science, Protein Serine-Threonine Kinases, 01 natural sciences, Biochemistry, CLK1, Glycogen Synthase Kinase 3, Structure-Activity Relationship, chemistry.chemical_compound, Drug Discovery, Quinazoline, [CHIM]Chemical Sciences, Humans, Potency, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein kinase A, Protein Kinase Inhibitors, Molecular Biology, ComputingMilieux_MISCELLANEOUS, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010405 organic chemistry, Kinase, Cyclin-dependent kinase 5, Organic Chemistry, Cyclin-Dependent Kinase 5, Protein-Tyrosine Kinases, Protein Structure, Tertiary, 3. Good health, 0104 chemical sciences, Molecular Docking Simulation, 010404 medicinal & biomolecular chemistry, chemistry, Quinazolines, Molecular Medicine, Casein kinase 1, Protein Kinases
Abstract

New pyrido[3,4-g]quinazoline derivatives were prepared and evaluated for their inhibitory potency toward 5 protein kinases (CLK1, DYRK1A, GSK3, CDK5, CK1). A related pyrido[4,3-h]quinazoline scaffold with an angular structure was also synthesized and its potency against the same protein kinase panel was compared to the analogous pyrido[3,4-g]quinazoline. Best results were obtained for 10-nitropyrido[3,4-g]quinazoline 4 toward CLK1 with nanomolar activities.

Published
2019
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3. Analogues synthétiques simplifiés de métabolites marins comme nouvel inhibiteur allostérique sélectif de la kinase Aurora B

Author

Sandrine Ruchaud, Béatrice Josselin, Blandine Baratte, Stéphane Bach, Jérôme Bignon, Hristo Nedev, Bogdan I. Iorga, Ali Al-Mourabit, Charlotte Juillet, Dina Boyarskaya, Ludmila Ermolenko, Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Station biologique de Roscoff (SBR), and Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Stereochemistry, kinase, Metabolite, [SDV]Life Sciences [q-bio], Allosteric regulation, Aurora B kinase, Cancer therapy, Antineoplastic Agents, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Adenosine Triphosphate, Allosteric Regulation, Cell Line, Tumor, Drug Discovery, medicine, Animals, Aurora Kinase B, Humans, cancer, [CHIM]Chemical Sciences, Aurora B, Mode of action, pyrrole-imidazole, Protein Kinase Inhibitors, Mitosis, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, 030304 developmental biology, mitosis, 0303 health sciences, allosteric inhibitor, 010405 organic chemistry, Kinase, Chemistry, Porifera, 0104 chemical sciences, Molecular Docking Simulation, Mechanism of action, Molecular Medicine, medicine.symptom
Abstract

International audience; Significant inhibition of Aurora B was achieved by the synthesis of simplified fragments of benzosceptrins and oroidin belonging to the marine pyrrole-2-aminoimidazoles metabolites isolated from sponges. Evaluation of kinase inhibition enabled the discovery of a synthetically accessible rigid acetylenic structural analogue EL-228 (1), whose structure could be optimized into the potent CJ2-150 (37). Here we present the synthesis of new inhibitors of Aurora B kinase, which is an important target for cancer therapy through mitosis regulation. The biologically oriented synthesis yielded several nanomolar inhibitors. The optimized compound CJ2-150 (37) showed a non-ATP competitive allosteric mode of action in a mixed-type inhibition for Aurora B kinase. Molecular docking identified a probable binding mode in the allosteric site "F" and highlighted the key interactions with the protein. We describe the improvement of the inhibitory potency and specificity of the novel scaffold as well as the characterization of the mechanism of action.; Une inhibition significative d'Aurora B a été obtenue par la synthèse de fragments simplifiés de benzosceptrines et d'oroïdine appartenant aux métabolites marins pyrrole-2-aminoimidazoles isolés à partir d'éponges. L'évaluation de l'inhibition de la kinase a permis la découverte d'un analogue structurel acétylénique rigide synthétiquement accessible EL-228 (1), dont la structure pourrait être optimisée dans le puissant CJ2-150 (37). Nous présentons ici la synthèse de nouveaux inhibiteurs de l'Aurora B kinase, qui est une cible importante pour le traitement du cancer par la régulation de la mitose. La synthèse biologiquement orientée a donné plusieurs inhibiteurs nanomolaires. Le composé optimisé CJ2-150 (37) a montré un mode d'action allostérique compétitif non ATP dans une inhibition de type mixte de la kinase Aurora B. L'arrimage moléculaire a identifié un mode de liaison probable dans le site allostérique «F» et a mis en évidence les interactions clés avec la protéine. Nous décrivons l'amélioration de la puissance inhibitrice et la spécificité du nouvel échafaudage ainsi que la caractérisation du mécanisme d'action.

Published
2021
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4. Discovery of simplified benzazole fragments derived from the marine benzosceptrin B as necroptosis inhibitors involving the receptor interacting protein Kinase-1

Author

Sandrine Ruchaud, Claire Delehouzé, Mohamed Souab, Agathe Vagneux, Ali Al-Mourabit, Stéphane Bach, Ludmila Ermolenko, Blandine Baratte, Hristo Nedev, Minh Tran, Béatrice Josselin, Mohamed Benchekroun, Bogdan I. Iorga, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CNRS, and Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
Programmed cell death, Fas-Associated Death Domain Protein, Necroptosis, Phenotypic screening, [SDV]Life Sciences [q-bio], [CHIM.INOR]Chemical Sciences/Inorganic chemistry, 01 natural sciences, Jurkat cells, Jurkat Cells, Structure-Activity Relationship, 03 medical and health sciences, RIPK1, Drug Discovery, Humans, [CHIM]Chemical Sciences, Pyrroles, Protein kinase A, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Pharmacology, 0303 health sciences, Binding Sites, Molecular Structure, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010405 organic chemistry, Chemistry, Organic Chemistry, Imidazoles, General Medicine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 0104 chemical sciences, Molecular Docking Simulation, Biochemistry, Drug Design, Receptor-Interacting Protein Serine-Threonine Kinases, Molecular mechanism, Fadd protein, Protein Binding
Abstract

International audience; With the aim to develop new chemical tools based on simplified natural metabolites to help deciphering the molecular mechanism of necroptosis, simplified benzazole fragments including 2-aminobenzimidazole and the 2-aminobenzothiazole analogs were prepared during the synthesis of the marine benzosceptrin B. Conpounds inhibiting the RIPK1 protein kinase were discovered. A library of 54 synthetic analogues were prepared and evaluated through a phenotypic screen using the inhibition of the necrotic cell death induced by TNF- in human Jurkat T cells deficient for the FADD protein. This article reports the design, synthesis and biological evaluation of a series of 2-aminobenzazoles on the necroptotic cell death through the inhibition of RIPK1 protein kinase. The 2-aminobenzimidazole and 2-aminobenzothiazole platforms presented herein can serve as novel chemical tools to study the molecular regulation of necroptosis and further develop lead drug candidates for chronic pathologies involving necroptosis.

Published
2020
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5. Identification of a new series of flavopiridol-like structures as kinase inhibitors with high cytotoxic potency

Author

Mouad Alami, Jean-Daniel Brion, Pascal Bonnet, Abdallah Hamze, Nada Ibrahim, Pierre Colas, Jean-François Peyrat, Thomas Robert, Samir Messaoudi, Jérôme Bignon, Stéphane Bach, Béatrice Josselin, Hélène Levaique, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Fédération de recherche de Roscoff (FR2424), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Messaoudi, Samir

Subjects
Stereochemistry, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Antineoplastic Agents, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Favopiridol, 01 natural sciences, Thiosugars, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, Thioether, Piperidines, Drug Discovery, Tumor Cells, Cultured, Structure–activity relationship, Cytotoxic T cell, Humans, Cytotoxicity, Kinase inhibition, Protein Kinase Inhibitors, 030304 developmental biology, Cell Proliferation, Pharmacology, chemistry.chemical_classification, Flavonoids, 0303 health sciences, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Kinase, Organic Chemistry, [CHIM.CATA] Chemical Sciences/Catalysis, General Medicine, [CHIM.CATA]Chemical Sciences/Catalysis, In vitro, structure-activity relationship. Highlights, 0104 chemical sciences, 3. Good health, Amino acid, Molecular Docking Simulation, chemistry, cytotoxicity, Drug Screening Assays, Antitumor, Protein Kinases
Abstract

International audience; In this work, unique structure of flavopiridol analogs bearing thiosugars, amino acids and heterocyclic moieties tethered to the flavopiridol via thioether and amine bonds mainly on its C ring have been prepared. The analogs bearing thioether-benzimidazoles as substituents have demonstrated high cytotoxic activity in vitro against up to seven cancer cell lines. Their cytotoxic effects are comparable to those of flavopiridol. The most active compound (13c) found after the structure-activity relationship (SAR) showed the best antiproliferative activity and was more efficient than the reference compound. In addition, compound 13c showed significant nanomolar inhibition against CDK9 and GSK3β protein kinases.

Published
2020
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6. Synthesis and biological evaluation of selected 7-azaindole derivatives as CDK9/Cyclin T and Haspin inhibitors

Author

Sandrine Ruchaud, Richard M. Beteck, Stéphane Bach, Lesetja J. Legoabe, Béatrice Josselin, Lianie Pieterse, Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), 12902608 - Legoabe, Lesetja Jan, 25159194 - Beteck, Richard Mbi, and 23347368 - Pieterse, Lianie

Subjects
7-Azaindole, [SDV]Life Sciences [q-bio], 01 natural sciences, 03 medical and health sciences, Suzuki reaction, Protein kinases, Bioorganic chemistry, [CHIM]Chemical Sciences, General Pharmacology, Toxicology and Pharmaceutics, Nuclear protein, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Biological evaluation, Cyclin, 0303 health sciences, CDK9/ Cyclin T, 010405 organic chemistry, Chemistry, Kinase, Haspin, Organic Chemistry, 3. Good health, 0104 chemical sciences, Anticancer, Biochemistry, Antimitotic Agent, Cyclin-dependent kinase 9
Abstract

The 7-azaindole scaffold attracts attention due to its value in the design of inhibitors of diseases related protein kinases. However, this scaffold has not been evaluated against Haploid germ cell-specific nuclear protein kinase (Haspin). Herein, we report the synthesis of a select set of 7-azaindole derivatives and their evaluation against Haspin. The compounds were also evaluated against CDK9/Cyclin T kinase. The synthesis of 7-azaindole derivatives was achieved through Suzuki coupling using appropriate halogenated 7-azaindole and boronic acids. Seven of the screened compounds exhibited activity as CDK9/Cyclin T and/or Haspin inhibitors in a nanomolar to low micromolar range. The most promising dual inhibiting compound 18c, exhibited an inhibitory potential of 0.206 µM against CDK9/Cyclin T and 0.118 µM against Haspin. The dual inhibition of CDK9/Cyclin T and Haspin could afford a potentially potent antimitotic agent of value in further anticancer studies.

Published
2020
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7. Synthesis and kinase inhibitory potencies of new pyrido[3,4-g]quinazolines substituted at the 8-position

Author

Pascale Moreau, Blandine Baratte, Stéphane Bach, Sandrine Ruchaud, Béatrice Josselin, Francis Giraud, Fabrice Anizon, Yannick J. Esvan, Institut de Chimie de Clermont-Ferrand (ICCF), SIGMA Clermont (SIGMA Clermont)-Institut de Chimie du CNRS (INC)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Fédération de recherche de Roscoff (FR2424), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
DYRK1A, 010405 organic chemistry, Kinase, Chemistry, Stereochemistry, pyrimidines, Cyclin-dependent kinase 5, [SDV]Life Sciences [q-bio], Organic Chemistry, Fused azines, 01 natural sciences, pyridoquinazolines, 0104 chemical sciences, 3. Good health, isoquinolines, CLK1, chemistry.chemical_compound, Quinazoline, Moiety, Potency, [CHIM]Chemical Sciences, Casein kinase 1, ComputingMilieux_MISCELLANEOUS
Abstract

International audience; As part of the structure-activity relationship study undertaken around the pyrido[3,4-g]quinazoline moiety, new derivatives substituted at the 8-position were synthesized and evaluated regarding their ability to inhibit various protein kinases (CDK5, CLK1, DYRK1A, CK1, GSK3). Most active compound exhibited a nanomolar potency toward CLK1, demonstrating that substitution at 8-position is compatible with CLK1 inhibition.

Published
2020
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8. Design of new disubstituted imidazo[1,2- b ]pyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation

Author

Matthieu Place, Omid Feizbakhsh, Amandine Bescond, Apirat Chaikuad, Agnes Chartier, Sandrine Ruchaud, Frédéric Buron, Sylvain Routier, Julien Duez, Stefan Knapp, Dominique Marie, Blandine Baratte, Nathalie Desban, Stéphane Bach, Fabrice Carles, Jonathan Elie, Xavier Fant, Sami Ben Salah, Béatrice Josselin, Sabine Berteina-Raboin, Pascal Bonnet, Institut de Chimie Organique et Analytique (ICOA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Fédération de recherche de Roscoff (FR2424), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Phophorylation de protéines et Pathologies Humaines (P3H), Station biologique de Roscoff [Roscoff] (SBR), 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), MArine Phototrophic Prokaryotes (MAPP), Adaptation et diversité en milieu marin (AD2M), 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)-Station biologique de Roscoff [Roscoff] (SBR), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
imidazopyridazine, Cell division, [SDV]Life Sciences [q-bio], Apoptosis, 01 natural sciences, Histones, Pyridazine, chemistry.chemical_compound, Drug Discovery, Phosphorylation, ComputingMilieux_MISCELLANEOUS, Osteosarcoma, co-crystallisation and docking, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Chemistry, Intracellular Signaling Peptides and Proteins, General Medicine, haspin kinase, Anticancer Biological, 3. Good health, Cell biology, Molecular Docking Simulation, Pyridazines, Histone phosphorylation, Research Article, Research Paper, Indazoles, Aurora B kinase, Antineoplastic Agents, Bone Neoplasms, RM1-950, macromolecular substances, Cyclin B, Protein Serine-Threonine Kinases, Structure-Activity Relationship, Cell Line, Tumor, CDC2 Protein Kinase, Humans, [CHIM]Chemical Sciences, Amino Acid Sequence, Protein kinase A, Protein Kinase Inhibitors, Mitosis, Cell Proliferation, Pharmacology, cellular effects, 010405 organic chemistry, 3d spheroids, 0104 chemical sciences, enzymes and coenzymes (carbohydrates), 010404 medicinal & biomolecular chemistry, Therapeutics. Pharmacology, Drug Screening Assays, Antitumor
Abstract

Haspin is a mitotic protein kinase required for proper cell division by modulating Aurora B kinase localisation and activity as well as histone phosphorylation. Here a series of imidazopyridazines based on the CHR-6494 and Structure Activity Relationship was established. An assessment of the inhibitory activity of the lead structures on human Haspin and several other protein kinases is presented. The lead structure was rapidly optimised using a combination of crystal structures and effective docking models, with the best inhibitors exhibiting potent inhibitory activity on Haspin with IC50 between 6 and 100 nM in vitro. The developed inhibitors displayed anti-proliferative properties against various human cancer cell lines in 2D and spheroid cultures and significantly inhibited the migration ability of osteosarcoma U-2 OS cells. Notably, we show that our lead compounds are powerful Haspin inhibitors in human cells, and did not block G2/M cell cycle transition due to improved selectivity against CDK1/CyclinB., Graphical Abstract

Published
2020
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9. New pyrido[3,4-g]quinazoline derivatives as CLK1 and DYRK1A inhibitors: synthesis, biological evaluation and binding mode analysis

Author

Yannick J. Esvan, Pascale Moreau, Andreas C. Joerger, Fabrice Anizon, Helmi Tazarki, Stéphane Bach, Martin Schröder, Blandine Baratte, Deep Chatterjee, Wael Zeinyeh, Jameleddine Khiari, Béatrice Josselin, Sandrine Ruchaud, Francis Giraud, Stefan Knapp, Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Clermont-Ferrand (ICCF), SIGMA Clermont (SIGMA Clermont)-Institut de Chimie du CNRS (INC)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Institut Supérieur de l'Enseignement et de la Formation Continue [Tunis] (ISEFC), Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Plate-forme de criblage d'inhibiteurs de protéines kinases=Kinase Inhibitor Specialized Screening facility (KISSf), Fédération de recherche de Roscoff (FR2424), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Intégrative (LBI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Université Clermont Auvergne (UCA)

Subjects
DYRK1A, Protein Conformation, [SDV]Life Sciences [q-bio], CLK1, Chemistry Techniques, Synthetic, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Protein Serine-Threonine Kinases, 01 natural sciences, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Cell Line, Tumor, Drug Discovery, Quinazoline, Humans, [CHIM]Chemical Sciences, Viability assay, Tyrosine, DYRKA, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Pharmacology, 0303 health sciences, CLK1, DYRKA, Kinase inhibitors, Pyridoquinazolines, 010405 organic chemistry, Kinase, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Cyclin-dependent kinase 5, Organic Chemistry, Pyridoquinazolines, General Medicine, Protein-Tyrosine Kinases, 3. Good health, 0104 chemical sciences, Molecular Docking Simulation, chemistry, Biochemistry, Kinase inhibitors, Drug Design, Quinazolines, Casein kinase 1, Protein Binding
Abstract

International audience; Cdc2-like kinase 1 (CLK1) and dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) are involved in the regulation of alternative pre-mRNA splicing. Dysregulation of this process has been linked to cancer progression and neurodegenerative diseases, making CLK1 and DYRK1A important therapeutic targets. Here we describe the synthesis of new pyrido[3,4-g]quinazoline derivatives and the evaluation of the inhibitory potencies of these compounds toward CDK5, CK1, GSK3, CLK1 and DYRK1A. Introduction of aminoalkylamino groups at the 2-position resulted in several compounds with low nanomolar affinity and selective inhibition of CLK1 and/or DYRK1A. Their evaluation on several immortalized or cancerous cell lines showed varying degree of cell viability reduction. Co-crystal structures of CLK1 with two of the most potent compounds revealed two alternative binding modes of the pyrido[3,4-g]quinazoline scaffold that can be exploited for future inhibitor design.

Published
2019
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10. Synthesis and evaluation of 7-azaindole derivatives bearing benzocycloalkanone motifs as protein kinase inhibitors

Author

Lesetja J. Legoabe, Stéphane Bach, Malikotsi A. Qhobosheane, Sandrine Ruchaud, Béatrice Josselin, Richard M. Beteck, Jacobus P. Petzer, Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), 10727388 - Petzer, Jacobus Petrus, 12902608 - Legoabe, Lesetja Jan, 25159194 - Beteck, Richard Mbi, and 27836576 - Qhobosheane, Malikotsi A.

Subjects
Benzocycloalkanone, Indoles, 7-Azaindole, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Pharmaceutical Science, Protein Serine-Threonine Kinases, 01 natural sciences, Biochemistry, Protein kinase, Structure-Activity Relationship, CDK9/CyclinT, Drug Discovery, Humans, [CHIM]Chemical Sciences, Structure–activity relationship, Protein kinase A, Protein Kinase Inhibitors, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Biological evaluation, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Kinase, Chemistry, Haspin, Organic Chemistry, Intracellular Signaling Peptides and Proteins, Dual inhibitor, Ketones, Structure-activity relationship, Cyclin-Dependent Kinase 9, 3. Good health, 0104 chemical sciences, Molecular Docking Simulation, 010404 medicinal & biomolecular chemistry, Oncology, Molecular Medicine, Cyclin-dependent kinase 9
Abstract

Protein kinases are important drug targets, especially in the area of oncology. This paper reports the synthesis and biological evaluation of new 7-azaindole derivatives bearing benzocycloalkanone motifs as potential protein kinase inhibitors. Four compounds 8g, 8h, 8i, and 8l were discovered to inhibit cyclin-dependent kinase 9 (CDK9/CyclinT) and/or Haspin kinase in the micromolar to nanomolar range. 8l was identified as the most potent Haspin inhibitor (IC50 = 14 nM), while 8g and 8h acted as dual inhibitors of CDK9/CyclinT and Haspin. These novel compounds constitute a promising starting point for the discovery of dual protein kinase inhibitors that have potential to be developed as anticancer agents, since both CDK9/CyclinT and Haspin are considered to be drug targets in oncology.

Published
2020
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11. Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3

Author

Pierre-Yves Renard, Marina Naldi, Joel L. Sussman, Stéphane Bach, Rémy Le Guével, Nunzio Denora, Jacques-Philippe Colletier, Sylvain Routier, Ludovic Jean, Leonardo Pisani, Marco Catto, Béatrice Josselin, Nicolas Coquelle, Israel Silman, Rosa Maria Iacobazzi, Frédéric Buron, Manuela Bartolini, Killian Oukoloff, Sandrine Ruchaud, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), 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)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), 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), 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)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Alma Mater Studiorum University of Bologna (UNIBO), Plate-forme ImPACcell (ImPACcell), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Phophorylation de protéines et Pathologies Humaines (P3H), Station biologique de Roscoff [Roscoff] (SBR), 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), Università degli studi di Bari Aldo Moro (UNIBA), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Weizmann Institute of Science [Rehovot, Israël], Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex SynOrg (ANR-11-LABX-0029) is acknowledged for a PhD fellowship to K. O. and the Agence Nationale de la Recherche (project MultiClick, grant number ANR-12-BS07-008-01) for financial support. This work was also partially supported by the INSA Rouen, Rouen Normandy University, the Centre National de la Recherche Scientifique and the Region Normandie (CRUNCh network)., Oukoloff K., Coquelle N., Bartolini M., Naldi M., Le Guevel R., Bach S., Josselin B., Ruchaud S., Catto M., Pisani L., Denora N., Iacobazzi R.M., Silman I., Sussman J.L., Buron F., Colletier J.-P., Jean L., Routier S., Renard P.-Y., Institut de Chimie Organique Fine (IRCOF), 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)-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), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fédération de recherche de Roscoff (FR2424), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), ANR-11-LABX-0029,SYNORG,Synthèse Organique : des molécules au vivant(2011), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), and Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Kinase, [SDV]Life Sciences [q-bio], [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Ligands, Crystallography, X-Ray, 01 natural sciences, Antineoplastic Agent, chemistry.chemical_compound, Glycogen Synthase Kinase 3, Synthesis, GSK-3, Drug Discovery, Dog, Enzyme Inhibitor, Enzyme Inhibitors, Cytotoxicity, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, 0303 health sciences, Crystallography, Molecular Structure, Synthesi, General Medicine, Alzheimer's disease, Acetylcholinesterase, Tacrine, Pharmacophore, medicine.drug, Human, SAR, Glycogen synthase kinase-3, Stereochemistry, Cell Survival, Cyclin-dependent kinase 5, Antineoplastic Agents, Ligand, Kinases, 03 medical and health sciences, Structure-Activity Relationship, Dogs, medicine, [CHIM.CRIS]Chemical Sciences/Cristallography, Structure–activity relationship, [CHIM]Chemical Sciences, Animals, Humans, 030304 developmental biology, Cell Proliferation, Pharmacology, Dose-Response Relationship, Drug, 010405 organic chemistry, Cell growth, Animal, Organic Chemistry, Triazoles, 0104 chemical sciences, chemistry, Drug Design, Butyrylcholinesterase, Triazole, Drug Screening Assays, Antitumor, Linker
Abstract

International audience; Both cholinesterases (AChE and BChE) and kinases, such as GSK-3α/β, are associated with the pathology of Alzheimer's disease. Two scaffolds, targeting AChE (tacrine) and GSK-3α/β (valmerin) simultaneously, were assembled, using copper(I)-catalysed azide alkyne cycloaddition (CuAAC), to generate a new series of multifunctional ligands. A series of eight multi-target directed ligands (MTDLs) was synthesized and evaluated in vitro and in cell cultures. Molecular docking studies, together with the crystal structures of three MTDL/TcAChE complexes, with three tacrine-valmerin hybrids allowed designing an appropriate linker containing a 1,2,3-triazole moiety whose incorporation preserved, and even increased, the original inhibitory potencies of the two selected pharmacophores toward the two targets. Most of the new derivatives exhibited nanomolar affinity for both targets, and the most potent compound of the series displayed inhibitory potencies of 9.5 nM for human acetylcholinesterase (hAChE) and 7 nM for GSK-3α/β. These novel dual MTDLs may serve as suitable leads for further development, since, in the micromolar range, they exhibited low cytotoxicity on a panel of representative human cell lines including the human neuroblastoma cell line SH-SY5Y. Moreover, these tacrine-valmerin hybrids displayed a good ability to penetrate the blood-brain barrier (BBB) without interacting with efflux pumps such as P-gp.

Published
2019
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