7AVQ

Crystal structure of haspin in complex with disubstituted imidazo[1,2- b]pyridazine inhibitor (compound 12)

Summary for 7AVQ

• Entry DOI: 10.2210/pdb7avq/pdb
• Descriptor: Serine/threonine-protein kinase haspin, (2~{R})-2-[[3-(2~{H}-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl]amino]butan-1-ol, SODIUM ION, ... (6 entities in total)
• Functional Keywords: kinase, haspin, gsg2, inhibitor, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 41359.20

Authors

Chaikuad, A.,Bonnet, P.,Routier, S.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2020-11-05, release date: 2020-11-18, Last modification date: 2024-01-31)

Primary citation

Elie, J.,Feizbakhsh, O.,Desban, N.,Josselin, B.,Baratte, B.,Bescond, A.,Duez, J.,Fant, X.,Bach, S.,Marie, D.,Place, M.,Ben Salah, S.,Chartier, A.,Berteina-Raboin, S.,Chaikuad, A.,Knapp, S.,Carles, F.,Bonnet, P.,Buron, F.,Routier, S.,Ruchaud, S.
Design of new disubstituted imidazo[1,2- b ]pyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation.
J Enzyme Inhib Med Chem, 35:1840-1853, 2020

PubMed 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 IC between 6 and 100 nM . 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.

PubMed: 33040634
DOI: 10.1080/14756366.2020.1825408

Experimental method

X-RAY DIFFRACTION (1.65 Å)