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

DOI: 10.1080/14756366.2020.1825408 DOI Help

Authors: Jonathan Elie (Universite d’Orleans, UMR CNRS 7311) , Omid Feizbakhsh (Sorbonne Universite/CNRS UMR8227) , Nathalie Desban (Sorbonne Universite/CNRS UMR8227) , Béatrice Josselin (Sorbonne Universite/CNRS UMR8227; Sorbonne Universit e/CNRS FR242) , Blandine Baratte (Sorbonne Universite/CNRS UMR8227; Sorbonne Universit e/CNRS FR242) , Amandine Bescond (Sorbonne Universite/CNRS UMR8227) , Julien Duez (Sorbonne Universite/CNRS UMR8227) , Xavier Fant (Sorbonne Universite/CNRS UMR8227) , Stéphane Bach (Sorbonne Universite/CNRS UMR8227; Sorbonne Universite/CNRS FR242) , Dominique Marie (Sorbonne Universite/CNRS UMR714) , Matthieu Place (Universite d’Orleans, UMR CNRS 7311) , Sami Ben Salah (Universite d’Orleans, UMR CNRS 7311) , Agnes Chartier (Universite d’Orleans, UMR CNRS 7311) , Sabine Berteina-raboin (Universite d’Orleans, UMR CNRS 7311) , Apirat Chaikuad (Structure Genomics Consortium, Johann Wolfgang Goethe University) , Stefan Knapp (Structure Genomics Consortium, Johann Wolfgang Goethe University) , Fabrice Carles (Universite d’Orleans, UMR CNRS 7311) , Pascal Bonnet (Universite d’Orleans, UMR CNRS 7311) , Frédéric Buron (Universite d’Orleans, UMR CNRS 7311) , Sylvain Routier (Universite d’Orleans, UMR CNRS 7311) , Sandrine Ruchaud (Sorbonne Universite/CNRS UMR714)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Enzyme Inhibition And Medicinal Chemistry , VOL 35 , PAGES 1840 - 1853

State: Published (Approved)
Published: January 2020
Diamond Proposal Number(s): 10619

Open Access Open Access

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.

Journal Keywords: Imidazopyridazine; Haspin kinase; co-crystallisation and docking; cellular effects; 3D spheroids

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

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Design of new disubstituted imidazo 1 2 b pyridazine derivatives as selective Haspin inhibitors Synthesis binding mode and anticancer biological.pdf

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