BAY-1816032

BAY 1816032 is an exquisitely selective ATP-competitive inhibitor of BUB1 kinase with long residence time (t1/2 of 87 or 203 minutes, measured by kPCA or SPR, respectively). In the DiscoveRx panel of 403 kinases, BAY 1816032 gives a Kd of 3.3 nM, whereas the next inhibited kinases are LOK (Kd =57 nM) and DMPK2 (Kd = 850 nM). The authors went further to demonstrate that BAY 1816032 at 10 uM does not inhibit pERM, the physiological substrate of LOK, whereas erlotinib (Kd of 19 nM for LOK) does at compound concentration of 10 uM. The cellular potency of BAY 1816032 has been demonstrated by inhibition of histone H2A-Thr120 phosphorylation with IC50 of 29 +/- 23 nM. In nude mice, BAY 1816032 dosed up to 150 mg/kg orally BID has demonstrated dose-dependent inhibition of phospho-Thr120 histone H2A in skin tissues. This is also the dose where combination efficacy has been demonstrated with BAY 1816032 added to paclitaxel in SUM-149 TNBC model, or BAY 1816032 added to olaparib in BRCA-1 mutated MDA-MB-436 TNBC model. Please note that this compound has moderate half-life (1.8 h) in mice, thus BID (twice daily) dosing is likely required. This probe is useful to dissect kinase catalytic and scaffolding function of BUB1.

BAY-1816032 is a useful chemical tool to investigate the effects of inhibition of human BUB1 in human cancer cells lines, in vitro and in murine xenograft studies. Suitable in vivo doses in murine models are 25 or 50 mg/kg p.o., given twice daily. The compound appears generally well tolerated in toxicity studies, so it is suitable for investigating combinations with other oncology therapeutics.