Design of new disubstituted imidazo[1,2- b ]pyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation
| العنوان: | Design of new disubstituted imidazo[1,2- b ]pyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation |
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| المؤلفون: | 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 |
| المساهمون: | 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), 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) |
| المصدر: | Journal of Enzyme Inhibition and Medicinal Chemistry Journal of Enzyme Inhibition and Medicinal Chemistry, 2020, 35 (1), pp.1840-1853. ⟨10.1080/14756366.2020.1825408⟩ Journal of Enzyme Inhibition and Medicinal Chemistry, Informa Healthcare, 2020, 35 (1), pp.1840-1853. ⟨10.1080/14756366.2020.1825408⟩ Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 35, Iss 1, Pp 1840-1853 (2020) article-version (VoR) Version of Record |
| بيانات النشر: | HAL CCSD, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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 |
| اللغة: | English |
| تدمد: | 1475-6366 1475-6374 |
| DOI: | 10.1080/14756366.2020.1825408⟩ |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2c123cd3addc29babf164e9067364ee8 https://hal.science/hal-03004407 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2c123cd3addc29babf164e9067364ee8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14756366 14756374 |
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| DOI: | 10.1080/14756366.2020.1825408⟩ |