7ops
Crystal structure of haspin in complex with ZW282 (compound 2a)
Structural highlights
FunctionHASP_HUMAN Serine/threonine-protein kinase that phosphorylates histone H3 at 'Ser-3' (H3T3ph) during mitosis. This positions and activates AURKB and other components of the chromosomal passenger complex (CPC) at centromeres to ensure proper chromatid cohesion, metaphase alignment and normal progression through the cell cycle.[1] [2] [3] [4] [5] Publication Abstract from PubMedHaspin (haploid germ cell-specific nuclear protein kinase) offers a potential target for the development of new anticancer drugs. Thus, the identification of new inhibitors targeting this protein kinase is of high interest. However, Haspin inhibitors developed to date show a poor selectivity profile over other protein kinases of the human kinome. Here, we identified a new pyridoquinazoline based inhibitor (4), with excellent inhibitory activity and selectivity for Haspin (IC50 of 50 nM). We describe the structure-activity relationship study including the evaluation of this inhibitor on a large panel of 486 kinases as well as on immortalized or cancer cell lines. In addition, we determined the binding mode of analog 2a in complex with Haspin using X-ray crystallography. Synthesis and biological evaluation of Haspin inhibitors: Kinase inhibitory potency and cellular activity.,Zeinyeh W, Esvan YJ, Josselin B, Defois M, Baratte B, Knapp S, Chaikuad A, Anizon F, Giraud F, Ruchaud S, Moreau P Eur J Med Chem. 2022 Apr 9;236:114369. doi: 10.1016/j.ejmech.2022.114369. PMID:35447555[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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