Abstract
The catalytic function of BUB1 is required for chromosome arm resolution and positioning of the chromosomal passenger complex for resolution of spindle attachment errors and plays only a minor role in spindle assembly checkpoint activation. Here, we present the identification and preclinical pharmacologic profile of the first BUB1 kinase inhibitor with good bioavailability. The Bayer compound library was screened for BUB1 kinase inhibitors and medicinal chemistry efforts to improve target affinity and physicochemical and pharmacokinetic parameters resulting in the identification of BAY 1816032 were performed. BAY 1816032 was characterized for kinase selectivity, inhibition of BUB1 signaling, and inhibition of tumor cell proliferation alone and in combination with taxanes, ATR, and PARP inhibitors. Effects on tumor growth in vivo were evaluated using human triple-negative breast xenograft models. The highly selective compound BAY 1816032 showed long target residence time and induced chromosome mis-segregation upon combination with low concentrations of paclitaxel. It was synergistic or additive in combination with paclitaxel or docetaxel, as well as with ATR or PARP inhibitors in cellular assays. Tumor xenograft studies demonstrated a strong and statistically significant reduction of tumor size and excellent tolerability upon combination of BAY 1816032 with paclitaxel or olaparib as compared with the respective monotherapies. Our findings suggest clinical proof-of-concept studies evaluating BAY 1816032 in combination with taxanes or PARP inhibitors to enhance their efficacy and potentially overcome resistance.
Highlights
Cell-cycle deregulation represents one of the classical hallmarks of cancer [1], and cell-cycle arrest is the predominant mode of action of a lot of the cancer drugs on the market including "antimitotics" such as taxanes and vinca alkaloids
The concept of cell-cycle checkpoint regulation offers a novel approach to cancer treatment: inactivation of cell-cycle checkpoints is considered to drive tumor cells into cell division despite DNA damage or unattached/misattached chromosomes resulting in a lethal degree of DNA damage or aneuploidy [2]
We describe the preclinical profile of BAY 1816032, a novel, bioavailable inhibitor of the catalytic activity of the mitotic checkpoint protein BUB1, which is involved in centromere cohesion and attachment error correction
Summary
Cell-cycle deregulation represents one of the classical hallmarks of cancer [1], and cell-cycle arrest is the predominant mode of action of a lot of the cancer drugs on the market including "antimitotics" such as taxanes and vinca alkaloids. The concept of cell-cycle checkpoint regulation offers a novel approach to cancer treatment: inactivation of cell-cycle checkpoints is considered to drive tumor cells into cell division despite DNA damage or unattached/misattached chromosomes resulting in a lethal degree of DNA damage or aneuploidy [2]. The spindle assembly checkpoint (SAC, known as spindle checkpoint or mitotic checkpoint) controls the accurate attachment of microtubules of the spindle device to the kine-. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Current address for A.E. Fernandez-Montalvan: Servier Research Institute,125, Chemin de Ronde, 78290 Croissy-sur-Seine, France
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