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KIF11 inhibition for glioblastoma treatment: reason to hope or a struggle with the brain?
BMC Cancer, 06/26/09

Valensin S et al. - In a study to assess the relevance of the anti-mitotic Kinesin-like protein KIF11 in human glioblastomas (GBM) cell-lines, it was reported that in the area of cell cycle inhibition, KIF11 is critical for proper spindle assembly and represents an attractive anticancer target. KIF11 inhibitors, when able to permeate the blood-brain-barrier, could represent an interesting class of anticancer drugs with low neurotoxic effects in treatment of brain tumor.

• Due to the brain location of the tumor, potential target inhibition for anticancer therapy must exhibit a manageable neurotoxicity profile in the concentration range in which the compounds show anti-proliferative activity.
• Kinesin KIF11 inhibition by small molecules such as Monastrol or Ispinesib is currently under investigation in the field of malignant tumors.
• The relevance of the anti-mitotic Kinesin-like protein KIF11 in human GBM cell-lines was assessed.

• The target was validated using a set of well characterised and potentially specific small molecule inhibitors of KIF11: an ispinesib analog, Monastrol, a Merck compound and 3 simplified derivatives of the Merck compound.
• Following an in silico selection, those compounds predicted to bear a favorable BBB permeation profile were assessed for their phenotypic effect on cell lines derived both from primary (U87MG) as well as treated (DBTRG-05-MG) glioblastomas.
• For some compounds, the data could be compared to their effect on normal human astrocytes, as well as their neurotoxicity on primary rat cortical neurons.
• Ispinesib analogue 1 showed an anti-proliferative effect on GBM cell lines by blocking them in the G2/M phase in a concentration range which was shown to be harmless to primary rat cortical neurons.
• Ispinesib analog increased caspase 3/7-induced apoptosis in U87MG cells.

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