Leiden University Scholarly Publications

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Bosman, R.E.J. (2022)

Discovery of BUB1 kinase inhibitors for the treatment of cancer

Doctoral Thesis
The spindle-assembly checkpoint (SAC) is a safety mechanism which secures accurate chromosome segregation during mitosis. BUB1, a serine/threonine kinase, is one of the proteins involved in this checkpoint and its inhibition is thought to have therapeutic potential for the treatment of cancer. Although the exact role of BUB1 in the SAC remains controversial, inhibition of its kinase function has previously been shown to reduce tumor size in mouse xenograft models when combined with paclitaxel. The research described in this thesis aimed to develop novel BUB1 kinase inhibitors for which high-throughput screening was used as starting point for drug discovery. Medicinal chemistry efforts were performed to improve potency after which the obtained inhibitors were further evaluated in cellular assays. In addition, the development of a cellular BUB1 target engagement assay is described. Hit optimization led to the discovery of two lead compounds with good physicochemical properties,...Show moreThe spindle-assembly checkpoint (SAC) is a safety mechanism which secures accurate chromosome segregation during mitosis. BUB1, a serine/threonine kinase, is one of the proteins involved in this checkpoint and its inhibition is thought to have therapeutic potential for the treatment of cancer. Although the exact role of BUB1 in the SAC remains controversial, inhibition of its kinase function has previously been shown to reduce tumor size in mouse xenograft models when combined with paclitaxel. The research described in this thesis aimed to develop novel BUB1 kinase inhibitors for which high-throughput screening was used as starting point for drug discovery. Medicinal chemistry efforts were performed to improve potency after which the obtained inhibitors were further evaluated in cellular assays. In addition, the development of a cellular BUB1 target engagement assay is described. Hit optimization led to the discovery of two lead compounds with good physicochemical properties, subnanomolar affinity for BUB1, good cellular BUB1 target engagement, acceptable selectivity over other kinases and a favorable in vitro ADME profile.
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Spindle-assembly checkpoint
Budding uninhibited by benzimidazole 1
Kinase inhibitors
Cancer
Target engagement
All authors
Bosman, R.E.J.
Supervisor
Stelt, M. van der; Boeckel, C.A.A. van
Co-supervisor
Buijsman, R.C.
Committee
Overkleeft, H.S.; Codee, J.D.C.; Artola Perez de Azanza, M.E.; Perrakis, A.; Kops, G.J.P.L.
Qualification
Doctor (dr.)
Awarding Institution
Leiden Institute of Chemistry (LIC), Faculty of Science, Leiden University
Date
2022-09-29
ISBN (print)
9789464239652