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Bioconjug Chem. 2015 Feb 18;26(2):225-34. doi: 10.1021/bc500464r. Epub 2015 Jan 29.

Bisubstrate inhibitor approach for targeting mitotic kinase Haspin.

Author information

1
University of Tartu , Institute of Chemistry, Ravila 14A, Tartu 50411, Estonia.

Abstract

During the past decade, the basophilic atypical kinase Haspin has emerged as a key player in mitosis responsible for phosphorylation of Thr3 residue of histone H3. Here, we report the construction of conjugates comprising an aromatic fragment targeted to the ATP-site of Haspin and a peptide mimicking the N-terminus of histone H3. The combination of effective solid phase synthesis procedures and a high throughput binding/displacement assay with fluorescence anisotropy readout afforded the development of inhibitors with remarkable subnanomolar affinity toward Haspin. The selectivity profiles of novel conjugates were established by affinity studies with a model basophilic kinase (catalytic subunit of cAMP-dependent protein kinase) and by a commercial 1-point inhibition assay with 43 protein kinases.

PMID:
25595038
DOI:
10.1021/bc500464r
[Indexed for MEDLINE]

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