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Purity: ≥98%
BAY 1217389 (BAY-1217389) is a novel, potent, orally bioavailable and selective inhibitor of the serine/threonine kinase monopolar spindle 1 (MPS1) (IC50 < 10 nM) with potential cancer activity by selectively binding to and inhibiting the activity of Mps1. This results in chromosomal misalignment and missegregation, accelerated mitosis, destabilization of the mitotic checkpoint complex, and inactivation of the spindle assembly checkpoint (SAC). In cancer cells that overexpress Mps1, this results in cell death.
| Targets |
Mps1 (IC50 = 0.63 nM)
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|---|---|
| ln Vitro |
BAY 1217389 has an IC50 value of 0.63±0.27 nmol/L in biochemical assays. The protein exhibits a high degree of selectivity towards other kinases and can bind to PDGFRβ (<10 nmol/L), Kit (between 10 and 100 nmol/L), CLK1, CLK2, CLK4, JNK1, JNK2, JNK3, LATS1, MAK, MAPKAP2, MERTK, p38β, PDGFRα, PIP5K1C, PRKD1, and RPS6KA5 (between 100 and 1,000 nmol/L). By causing an early exit from mitosis (referred to as "mitotic breakthrough") and thereby abrogating nocodazole-induced SAC activity, BAY1217389 induces multinuclearity and tumor cell death in cellular mechanistic assays. It has been discovered that it inhibits cell proliferation, with a median IC50 of 6.7 nmol/L (range: 3 to >300 nmol/L).
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| ln Vivo |
BAY 1217389 exhibits a moderate level of efficacy when used in monotherapy in tumor xenograft studies. In the tested species, its blood clearance is found to be low. The terminal half-lives were long and the Vss was high. Male Wistar rats (0.5 mg/kg) and female NMRI mice (1 mg/kg) are given oral BAY 1217389. Peak plasma concentrations are measured in the 1.5–7 hour time range. In rats, oral bioavailability is high, whereas in mice, it is moderate[1].
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| Enzyme Assay |
Through the phosphorylation of a biotinylated peptide (Biotin-Ahx-PWDPDDADITEILG-NH2), TRFRET-based in vitro kinase assays evaluate the inhibition of recombinant human Mps1 by BAY 1161909 or BAY 1217389. Standard assay conditions call for a 15-minute preincubation period between the kinase and test compound, followed by the addition of substrate and ATP at 10 μM to initiate the enzyme reaction.
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| Cell Assay |
Cells are seeded in the appropriate medium supplemented with 10% FCS into 96-well plates at densities ranging from 1,000 to 5,000 cells per well. Cells are treated with compound dilutions in quadruplicates after a 24-hour period. Adherent cells are stained with crystal violet and fixed with glutaraldehyde after an additional 96 hours. The company's software is used to calculate IC50 values through a 4-parameter fit.
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| Animal Protocol |
Mice: Female athymic NMRI nu/nu mice, aged 50 days, with an average body weight of 20-22 g, are utilized for tumor xenograft studies. Animals are randomized to treatment and control groups (8–10 mice / group) when tumors reach a size of 20–40 mm2, depending on the growth of the tumor model. They are then treated p.o. with vehicle (70% polyethylene glycol 400, 5% ethanol, 25% solutol), BAY 1161909, BAY 1217389, and/or paclitaxel. A2780cis tumor-bearing female NMRI nude mice are treated with paclitaxel (i.v., once at a dose of 24 mg/kg), BAY 1161909 (p.o., twice daily for two days at a dose of 2.5 mg/kg), and in combination with paclitaxel (i.v., once at a dose of 24 mg/kg) and BAY 1161909 (p.o., twice daily for two days at a dose of 1 mg/kg). This allows for the analysis of polyploidy and multinuclearity induction in vivo.
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| References |
| Molecular Formula |
C27H24F5N5O3
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|---|---|
| Molecular Weight |
561.5032
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| Exact Mass |
561.179
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| Elemental Analysis |
C, 57.75; H, 4.31; F, 16.92; N, 12.47; O, 8.55
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| CAS # |
1554458-53-5
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| Related CAS # |
1554458-53-5
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| PubChem CID |
78320750
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Index of Refraction |
1.617
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| LogP |
4.64
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
40
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| Complexity |
867
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC(C([H])([H])C([H])([H])N([H])C1=C([H])C(=NN2C1=NC([H])=C2C1C([H])=C([H])C(=C(C([H])([H])[H])C=1[H])C(N([H])C1([H])C([H])([H])C1([H])[H])=O)OC1C([H])=C([H])C(=C(C=1F)F)OC([H])([H])[H])(F)F
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| InChi Key |
WNEILUNVMHVMPH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H24F5N5O3/c1-14-11-15(3-6-17(14)26(38)35-16-4-5-16)19-13-34-25-18(33-10-9-27(30,31)32)12-22(36-37(19)25)40-21-8-7-20(39-2)23(28)24(21)29/h3,6-8,11-13,16,33H,4-5,9-10H2,1-2H3,(H,35,38)
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| Chemical Name |
N-cyclopropyl-4-[6-(2,3-difluoro-4-methoxyphenoxy)-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide
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| Synonyms |
BAY-1217389; BAY 1217389; BAY1217389
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| HS Tariff Code |
2934.99.9001
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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: ~100 mg/mL (~178.1 mM)
Ethanol: ~8 mg/mL (~14.3 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.45 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: ≥ 2.5 mg/mL (4.45 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7809 mL | 8.9047 mL | 17.8094 mL | |
| 5 mM | 0.3562 mL | 1.7809 mL | 3.5619 mL | |
| 10 mM | 0.1781 mL | 0.8905 mL | 1.7809 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02366949 | Completed | Drug: BAY1217389 Drug: Paclitaxel |
Medical Oncology | Bayer | February 27, 2015 | Phase 1 |
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