- 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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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.
- Bach, Stéphane,Baratte, Blandine,Ben Salah, Sami,Berteina-Raboin, Sabine,Bescond, Amandine,Bonnet, Pascal,Buron, Frédéric,Carles, Fabrice,Chaikuad, Apirat,Chartier, Agnes,Desban, Nathalie,Duez, Julien,Elie, Jonathan,Fant, Xavier,Feizbakhsh, Omid,Josselin, Béatrice,Knapp, Stefan,Marie, Dominique,Place, Matthieu,Routier, Sylvain,Ruchaud, Sandrine
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- Discovery of imidazo[1,2-b]pyridazines as IKKβ inhibitors. Part 3: Exploration of effective compounds in arthritis models
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We have discovered imidazo[1,2-b]pyridazine derivatives that show suppressive activity of inflammation in arthritis models. We optimized the substructures of imidazo[1,2-b]pyridazine derivatives to combine potent IKKβ inhibitory activity, TNFα inhibitory
- Shimizu, Hiroki,Yamasaki, Tomonori,Yoneda, Yoshiyuki,Muro, Fumihito,Hamada, Tomoaki,Yasukochi, Takanori,Tanaka, Shinji,Toki, Tadashi,Yokoyama, Mika,Morishita, Kaoru,Iimura, Shin
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scheme or table
p. 4550 - 4555
(2011/09/12)
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- 6-AMINOIMIDAZO[1,2-b]PYRIDAZINE ANALOGS AS RHO KINASE INHIBITORS FOR THE TREATMENT OF RHO KINASE-MEDIATED DISEASES AND CONDITIONS
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Methods for using 6-aminoimidazo[1,2-b]pyridazine analogs are disclosed herein to treat rho kinase-mediated diseases or rho kinase-mediated conditions, including controlling intraocular pressure and treating glaucoma, are disclosed. Ophthalmic pharmaceutical compositions useful in the treatment of eye diseases such as glaucoma, and additionally useful for controlling intraocular pressure, the compositions comprising an effective amount of 6-aminoimidazo[1,2-b]pyridazine analogs, are disclosed herein.
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Page/Page column 7
(2008/12/06)
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