BAY-1816032
目录号 : GC32824An inhibitor of BUB1 kinase
Cas No.:1891087-61-8
Sample solution is provided at 25 µL, 10mM.
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BAY-1816032 is an inhibitor of the mitotic checkpoint serine/threonine protein kinase BUB1 (IC50 = 6.1 nM).1 It is selective for BUB1 over FLT3 (IC50 = 4.2 ?M) and 15 other kinases (IC50s = >10 ?M for all). BAY-1816032 inhibits proliferation of a variety of cancer cells (median IC50 = 1.4 ?M) and acts synergistically with the mitotic inhibitor paclitaxel to increase the rate of chromosomal segregation defects during mitosis in HeLa cells. It reduces tumor growth in a SUM149 mouse xenograft model when administered at a dose of 25 mg/kg and has an additive effect on reducing tumor growth when used in combination with paclitaxel in the same model.
1.Siemeister, G., Mengel, A., Fernández-Montalván, A.E., et al.Inhibition of BUB1 kinase by BAY 1816032 sensitizes tumor cells toward taxanes, ATR, and PARP inhibitors in vitro and in vivoClin. Cancer Res.25(4)1404-1414(2019)
Cas No. | 1891087-61-8 | SDF | |
Canonical SMILES | COC1=C(NC2=NC(C3=NN(CC4=C(F)C=C(OCCO)C=C4F)C5=C3C=CC=C5)=NC=C2OC)C=CN=C1 | ||
分子式 | C27H24F2N6O4 | 分子量 | 534.51 |
溶解度 | DMSO : 25 mg/mL (46.77 mM);Water : < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 1.8709 mL | 9.3544 mL | 18.7087 mL |
5 mM | 0.3742 mL | 1.8709 mL | 3.7417 mL |
10 mM | 0.1871 mL | 0.9354 mL | 1.8709 mL |
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1. 首先保证母液是澄清的;
2.
一定要按照顺序依次将溶剂加入,进行下一步操作之前必须保证上一步操作得到的是澄清的溶液,可采用涡旋、超声或水浴加热等物理方法助溶。
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Inhibition of BUB1 Kinase by BAY 1816032 Sensitizes Tumor Cells toward Taxanes, ATR, and PARP Inhibitors In Vitro and In Vivo
Clin Cancer Res 2019 Feb 15;25(4):1404-1414.PMID:30429199DOI:10.1158/1078-0432.CCR-18-0628.
Purpose: 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. Experimental design: 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. Results: 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. Conclusions: 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.