BAY-1816032

BAY-1816032 is a potent and oral available BUB1 (budding uninhibited by benzimidazoles 1) kinase inhibitor with an IC50 of 7 nM.

BAY-1816032 inhibits BUB1 enzymatic activity with an IC50 of 7 nM, shows slow dissociation kinetics resulting in a long target residence time of 87 min, and an excellent selectivity on a panel of 395 kinases. Mechanistically BAY-1816032 abrogates nocodazole-induced Thr-120 phosphorylation of the major BUB1 target protein histone H2A in HeLa cells with an IC50 of 29 nM, induced lagging chromosomes and mitotic delay. Persistent lagging chromosomes and missegregation are observed upon combination with low concentrations of paclitaxel. Single agent BAY-1816032 inhibits proliferation of various tumor cell lines with a median IC50 of 1.4 μM and demonstrates synergy or additivity with paclitaxel or docetaxel in almost all cell lines evaluated (minimal combination index 0.3)[1].

In tumor xenograft studies BAY 1816032 only marginally inhibits tumor growth as single agent upon oral administration, however, upon combination with paclitaxel or docetaxel a strong and statistically significant reduction of tumor size as compared to the respective monotherapy is observed[1].

[1]. Siemeister G, et al. BAY 1816032, a novel BUB1 kinase inhibitor with potent antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Ishington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 287. doi:10.1158/1538-7445.AM2017-287