title: Probing the catalytic functions of Bub1 kinase using the small molecule inhibitors BAY-320 and BAY-524.
abstract: The kinase Bub1 functions in the spindle assembly checkpoint (SAC) and in chromosome congression, but the role of its catalytic activity remains controversial. Here, we use two novel Bub1 inhibitors, BAY-320 and BAY-524, to demonstrate potent Bub1 kinase inhibition both in vitro and in intact cells. Then, we compared the cellular phenotypes of Bub1 kinase inhibition in HeLa and RPE1 cells with those of protein depletion, indicative of catalytic or scaffolding functions, respectively. Bub1 inhibition affected chromosome association of Shugoshin and the chromosomal passenger complex (CPC), without abolishing global Aurora B function. Consequently, inhibition of Bub1 kinase impaired chromosome arm resolution but exerted only minor effects on mitotic progression or SAC function. Importantly, BAY-320 and BAY-524 treatment sensitized cells to low doses of Paclitaxel, impairing both chromosome segregation and cell proliferation. These findings are relevant to our understanding of Bub1 kinase function and the prospects of targeting Bub1 for therapeutic applications.
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Baron
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Conrad
authors.initials: C
authors.lastname: von Schubert
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Fabien
authors.initials: F
authors.lastname: Cubizolles
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Siemeister
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Hitchcock
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Mengel
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Schröder
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Amaury
authors.initials: A
authors.lastname: Fernández-Montalván
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: von Nussbaum
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Mumberg
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Erich A
authors.identifier: http://orcid.org/0000-0003-4835-5719
authors.initials: EA
authors.lastname: Nigg
mesh_terms: D002460:Cell Line; D002877:Chromosomes, Human / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; C584277:BUB1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: budding uninhibited by benzimidazoles 1; cell biology; chemical inhibitor; chromosome arm cohesion; chromosome segregation; human; paclitaxel; spindle assembly checkpoint