Inhibition of BUB1 kinase by Bay 1816032 sensitizes tumor cells toward taxanes, ATR, and PARP inhibitors in vitro and in vivo

Abstract

Purpose: The catalytic function of BUB1 is required for vivo were evaluated using human triple-negative breast chromosome arm resolution and positioning of the chromo-xenograft models. somal passenger complex for resolution of spindle attachment Results: The highly selective compound BAY 1816032 errors and plays only a minor role in spindle assembly check-showed long target residence time and induced chromosome point activation. Here, we present the identification and mis-segregation upon combination with low concentrations preclinical pharmacologic profile of the first BUB1 kinase of paclitaxel. It was synergistic or additive in combination with inhibitor with good bioavailability. paclitaxel or docetaxel, as well as with ATR or PARP inhibitors Experimental Design: The Bayer compound library was in cellular assays. Tumor xenograft studies demonstrated a screened for BUB1 kinase inhibitors and medicinal chem-strong and statistically significant reduction of tumor size and istry efforts to improve target affinity and physicochem-excellent tolerability upon combination of BAY 1816032 with ical and pharmacokinetic parameters resulting in the paclitaxel or olaparib as compared with the respective identification of BAY 1816032 were performed. BAY monotherapies. 1816032 was characterized for kinase selectivity, inhibi-Conclusions: Our findings suggest clinical proof-of-contion of BUB1 signaling, and inhibition of tumor cell cept studies evaluating BAY 1816032 in combination with proliferation alone and in combination with taxanes, taxanes or PARP inhibitors to enhance their efficacy and ATR, and PARP inhibitors. Effects on tumor growth in potentially overcome resistance.