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Purity: ≥98%
BAY-1816032 (BAY1816032) is a novel, potent and oral bioavailable inhibitor of BUB1 (budding uninhibited by benzimidazoles 1) kinase with anticancer effects. It inhibits BUB1 with an IC50 of 7 nM. BAY 1816032 featuring high potency, long target residence time and good oral bioavailablity. It 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 abrogated nocodazole-induced Thr-120 phosphorylation of the major BUB1 target protein histone H2A in HeLa cells with an IC50 of 29 nanomol/L, induced lagging chromosomes and mitotic delay. Persistent lagging chromosomes and missegregation were observed upon combination with low concentrations of paclitaxel. Single agent BAY 1816032 inhibited proliferation of various tumor cell lines with a median IC50 of 1.4 micromol/L and demonstrated synergy or additivity with paclitaxel or docetaxel in almost all cell lines evaluated (minimal combination index 0.3). In tumor xenograft studies BAY 1816032 only marginally inhibited 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 was observed. Intratumoral levels of phospho-Thr120 H2A were found to be strongly reduced, and no hints on drug-drug interactions were found. In line with the good tolerability in xenograft studies, no relevant findings from non-GLP 2 weeks toxicological studies in rat and dog were reported. Our findings validate the innovative concept of interference with mitotic checkpoints and justify clinical proof of concept studies evaluating BUB1 inhibitor BAY 1816032 in combination with taxanes in order to enhance their efficacy and potentially overcome resistance.
| ln Vitro |
With an IC50 of 7 nM and slow dissociation kinetics, BAY-1816032 inhibits BUB1 enzymatic activity. This leads to a great collection of 395 switches with an extended target residence time of 87 minutes. With an IC50 of 29 nM, BAY-1816032 inhibits the Thr-120 phosphorylation of the primary BUB1 target protein histone H2A in HeLa cells, resulting in lagging chromosomes and delayed mitotic divisions. Errors and lagging chromosomal persistence were seen in conjunction with low paclitaxel concentrations. With a median IC50 of 1.4 μM, the single drug BAY-1816032 reduced the proliferation of multiple cell lines in malignancies and shown enhanced efficacy when combined with paclitaxel in almost all of the cell lines that were assessed. Receptor cetaxel has a synergy or additivity (minimal combination) index of 0.3)[1].
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| ln Vivo |
as coupled with the paclitaxel cake cetaxel, BAY 1816032 significantly reduced the size of the tumor as compared to the respective therapies in tumor xenograft trials, where it only marginally suppressed tumor development when localized to the tumor [1].
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| References |
[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
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| Molecular Formula |
C27H24F2N6O4
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|---|---|
| Molecular Weight |
534.514072418213
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| CAS # |
1891087-61-8
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| SMILES |
COC1=C(NC2=NC(C3=NN(CC4=C(F)C=C(OCCO)C=C4F)C5=C3C=CC=C5)=NC=C2OC)C=CN=C1
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| Synonyms |
BAY1816032; BAY-1816032; BAY 1816032
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~25 mg/mL (~46.77 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.89 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.89 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.89 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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