Small molecule compound used to probe into the role of Mps1

The successful segregation of chromosomes in mitosis requires the timely coordination of cell cycle events to ensure the bipo¬lar attachment of sister chromatids via their kinetochores to the mitotic spindle before the initiation of anaphase. Deregulation of this process or uncoupling of its component parts can lead to aneuploidy and chromosomal instability (CIN), which are recog¬nized hallmarks of cancer.

One of the critical players in cell-cycle coordination is the dual-specificity kinase Mps1. Functional and localization experiments in mammalian cells have demonstrated that Mps1 is essential for the fidelity of the cell cycle and genomic stability.

Investigating how Mps1 kinase activity and its dynamic local¬ization during the cell cycle participate in the coordination of multiple cell cycle processes requires the ability to rapidly inhibit Mps1 kinase activity at specific phases of the cell cycle—a level of temporal control that cannot be attained using RNAi or other com¬mon genetic methods. Small molecules that are cell permeable and can inhibit Mps1 kinase activity with rapid and reversible kinetics may provide a powerful tool to probe cell cycle–related Mps1 func¬tions. However, most of the studies so far have used nonselective inhibitors - as such it has been difficult to assess the role played by Mps1.

In a recent study led by Dr. Nathanael Gray from the Harvard Medical School/ Dana-Farber Cancer Institute, the authors have discovered a selective Msp1 inhibitor by screening a kinase-directed library against a large panel of 352 diverse kinases. Not only the new inhibitor (named Msp1-IN-1) presented a good degree of specificity towards Msp1, but it is readily absorbed by the cells and rapidly blocks Msp1 function.

“The new compounds have a remarkable fit into the ATP binding site of the Msp1 kinase, which explains the observed specificity.” said Professor Stefan Knapp, from the SGC Oxford, responsible for the investigations on the molecular basis of the inhibitor activity. “The range of cellular effects arising from Msp1 inhibition can help us devise new strategies in fighting cancer”.

The study has also revealed that inhibition of Msp1 results in aneuploidy and a gradual loss of cell viability over several cell doublings. Recent evidence showed that administration of sublethal doses of paclitaxel (a checkpoint activator) combined with checkpoint inhi¬bition produced differential cell death responses in cancer versus normal cell lines. Taken together, these results open the possibilities of a therapeutic window for which inhibitors of Mps1 (and more gen¬erally against the SAC) may be used as potential anticancer agents.