Journal
CHEMBIOCHEM
Volume 18, Issue 8, Pages 790-798Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201600697
Keywords
5-iodotubercidin; association/dissociation kinetics; haspin; histoneH3; inhibitors; iodine
Funding
- Estonian Research Council [PUT7, IUT20-17]
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The atypical protein kinase haspin is a key player in mitosis by catalysing the phosphorylation of Thr3 in histoneH3, and thus ensuring the normal function of the chromosomal passenger complex. Here, we report the development of bisubstrate-analogue inhibitors targeting haspin. The compounds were constructed by linking 5-iodotubercidin to the Nterminus of histoneH3 peptide. The new conjugates show high affinity (sub-nanomolar K-D) towards haspin as well as slow kinetics of association and dissociation (residence time of several hours). This reflects a unique binding mode and translated into improved selectivity. The latter was confirmed in a biochemical binding/displacement assay with a panel of ten protein kinases, in a thermal shift assay with off-targets of 5-iodotubercidin (adenosine kinase and the Cdc2-like kinase family) and in assay with spiked HeLa cell lysate.
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