cb500789h_si_001.pdf (524.21 kB)
Synthesis and Biological Evaluation of Optimized Inhibitors of the Mitotic Kinesin Kif18A
journal contribution
posted on 2015-02-20, 00:00 authored by Joachim Braun, Martin M. Möckel, Tobias Strittmatter, Andreas Marx, Ulrich Groth, Thomas U. MayerThe mitotic spindle, a highly dynamic
structure composed of microtubules,
mediates the segregation of the previously duplicated genome into
the two nascent daughter cells. Errors in this process contribute
to pathology including tumor formation. Key for the shape and function
of the mitotic spindle are kinesins, molecular motor proteins that
convert chemical energy into mechanical work. Due to their fast mode
of action, small molecules are valuable tools to dissect the dynamic
functions of kinesins during mitosis. In this study, we report the
identification of optimized small molecule inhibitors of the mitotic
kinesin Kif18A. Using BTB-1, the first identified Kif18A inhibitor,
as a lead compound, we synthesized a collection of derivatives. We
demonstrate that some of the synthesized derivatives potently inhibited
the ATPase activity of Kif18A with a half maximal inhibitory concentration
(IC50) value in the low micromolar range. In vitro analysis of a panel of Kif18A-related kinesins revealed that the
two most potent compounds show improved selectivity compared to BTB-1.
Structure–activity relationship studies identified substituents
mediating undesired inhibitory effects on microtubule polymerization.
In summary, our study provides key insights into the mechanism of
action of BTB-1 and its analogs, which will have a great impact on
the further development of highly selective and bioactive Kif18A inhibitors.
Since Kif18A is frequently overexpressed in solid tumors, such compounds
are not only of great interest for basic research but also have the
potential to open up new strategies for the treatment of human diseases.