Bisubstrate Inhibitor Approach for Targeting Mitotic
Kinase Haspin
- Publication date
- Publisher
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