Probing the catalytic functions of Bub1 kinase using the small molecule inhibitors BAY-320 and BAY-524

The DNA in our cells is packaged into structures called chromosomes. When a cell divides, these chromosomes need to be copied and then correctly separated so that both daughter cells have a full set of genetic information. Errors in separating chromosomes can lead to the death of cells, birth defects or contribute to the development of cancer. Chromosomes are separated by an array of protein fibers called the mitotic spindle. A surveillance mechanism known as the spindle assembly checkpoint prevents the cell from dividing until all the chromosomes have properly attached to the spindle. A protein called Bub1 is a central element of the SAC. However, it was not clear whether Bub1 works primarily as an enzyme or as a scaffolding protein. Baron, von Schubert et al. characterized two new molecules that inhibit Bub1’s enzyme activity and used them to investigate what role the enzyme plays in the spindle assembly checkpoint in human cells. The experiments compared the effects of these inhibitors to the effects of other molecules that block the production of Bub1. Baron, von Schubert et al.’s findings suggest that Bub1 works primarily as a scaffolding protein, but that the enzyme activity is required for optimal performance. Further experiments show that when the molecules that inhibit the Bub1 enzyme are combined with paclitaxel – a widely used therapeutic drug – cancer cells have more difficulties in separating their chromosomes and divide less often. The new inhibitors used by Baron, von Schubert et al. will be useful for future studies of this protein in different situations. Furthermore, these molecules may have the potential to be used as anti-cancer therapies in combination with other drugs.