Kinesin Spindle Protein (KSP) is a motor protein that belongs to the family of the mitotic kinesins. Motor proteins are able to convert the energy generated by the hydrolysis of ATP into mechanical motion, allowing the movement of cellular components along microtubules. KSP activity is, in particular, related to the spindle pole separation during mitosis. Kinesin inhibition results in mitotic arrest and cell death. KSP expression is limited to the mitotic phase of cell division, so it represents an interesting target for the development of anticancer agents. Most of the inhibitors described in literature act through the binding with an induced-fit allosteric site. Very few ATP-site competitive inhibitors are nowadays available. We report herein the identification of a new scaffold for the development of potential ATP competitive KSP inhibitors. The preliminary biological evaluation of the synthesized derivatives demonstrates that 6-arylpyrimidine is an attractive scaffold for the development of novel ATP-competitive KSP inhibitors. Docking studies allowed to identify a plausible binding mode for these scaffolds within the ATP-binding pocket of the enzyme.

6-Arylpyrimidines as novel attractive scaffolds for ATP competitive KSP inhibition

FERRARESE, ALESSANDRO;MARZARO, GIOVANNI;MANZINI, PAOLO;GUIOTTO, ADRIANO;CHILIN, ADRIANA
2012

Abstract

Kinesin Spindle Protein (KSP) is a motor protein that belongs to the family of the mitotic kinesins. Motor proteins are able to convert the energy generated by the hydrolysis of ATP into mechanical motion, allowing the movement of cellular components along microtubules. KSP activity is, in particular, related to the spindle pole separation during mitosis. Kinesin inhibition results in mitotic arrest and cell death. KSP expression is limited to the mitotic phase of cell division, so it represents an interesting target for the development of anticancer agents. Most of the inhibitors described in literature act through the binding with an induced-fit allosteric site. Very few ATP-site competitive inhibitors are nowadays available. We report herein the identification of a new scaffold for the development of potential ATP competitive KSP inhibitors. The preliminary biological evaluation of the synthesized derivatives demonstrates that 6-arylpyrimidine is an attractive scaffold for the development of novel ATP-competitive KSP inhibitors. Docking studies allowed to identify a plausible binding mode for these scaffolds within the ATP-binding pocket of the enzyme.
6° Meeting Nuove Prospettive in Chimica Farmaceutica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/3018502
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