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MK-0731 (MK0731; MK 0731) is a potent kinesin spindle protein (KSP) inhibitor with potential anticancer activity. MK0731's suppression of kinesin spindle protein (KSP) can cause apoptosis in tumor cells overexpressing KSP, cell cycle arrest during the mitotic phase, and inhibition of mitotic spindle assembly.
| Targets |
KSP (IC50 = 2.2 nM)
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|---|---|
| ln Vitro |
MK-0731 binds to A2780 cell fluorescence with an EC50 of 2.7 nM (0.415-300 nM; 48 hours) [1]. MK-0731 exhibits a low affinity (IC50=20.5 μM) towards hERG channels.
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| ln Vivo |
MK-0731 (40 mg/kg/day; subcutaneous injection; for 11 days) has no effect on paclitaxel, however KB-v tumors that overexpress Pgp are inhibited in their growth [1]. A2780 xenografts treated with MK-0731 (2.5, 5, 10, 20, 40 mg/kg/day; minipump) show dose-proportional increases in tumor exposure and mitotic fragmentation [1]. Adsorption T1/2 of MK-0731 (1 mg/kg/day; intravenous catheter) is 1 hour, CL is 66 mL/min·kg, and Vss is 3 L/kg [1]. MK-0731's pharmacokinetic parameters [1]. Injection of rat intravenously (1 mg/kg) IV injection for dogs (0.4 mg/kg) Intravenous injection of rhesus monkey (0.4 mg/kg) T1/2 (hour) CL (mL/min/kg) = 1 2 1 66.7 15.1 23.1 L/kg Vss 3.0 1.6 2.3
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| Cell Assay |
Apoptosis analysis [1]
Cell Types: A2780 Cell Tested Concentrations: 0.415-300 nM Incubation Duration: 48 h Experimental Results: Induced apoptosis with EC50 of 2.7 nM. Able to induce mitotic arrest in cells with an IC50 of 19 nM[1]. |
| Animal Protocol |
Animal/Disease Models: Mice with bilateral xenografts of KB-3-1 and KB-v-1 cells [1]
Doses: 40 mpk Route of Administration: SC; qd×1; continued for 11 Day Experimental Results: Inhibited the growth of KB-v tumors that highly overexpressed Pgp, whereas paclitaxel (20 mpk; qd × 5) had no effect. |
| References |
[1]. Christopher D Cox, et al. Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-n-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer. J Med Chem. 2008 Jul 24;51(14):4239-52.
[2]. Kyle Holen, et al. A phase I trial of MK-0731, a kinesin spindle protein (KSP) inhibitor, in patients with solid tumors. Invest New Drugs. 2012 Jun;30(3):1088-95. |
| Molecular Formula |
C25H28N3O2F3
|
|---|---|
| Molecular Weight |
459.50392
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| Exact Mass |
459.21
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| Elemental Analysis |
C, 65.35; H, 6.14; F, 12.40; N, 9.14; O, 6.96
|
| CAS # |
845256-65-7
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| Related CAS # |
845256-65-7
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| Appearance |
Solid powder
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| SMILES |
CN1CC[C@@H]([C@@H](C1)F)N(C)C(=O)N2CC(=C[C@@]2(CO)C3=CC=CC=C3)C4=C(C=CC(=C4)F)F
|
| InChi Key |
MYBGWENAVMIGMM-GIFXNVAJSA-N
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| InChi Code |
InChI=1S/C25H28F3N3O2/c1-29-11-10-23(22(28)15-29)30(2)24(33)31-14-17(20-12-19(26)8-9-21(20)27)13-25(31,16-32)18-6-4-3-5-7-18/h3-9,12-13,22-23,32H,10-11,14-16H2,1-2H3/t22-,23+,25-/m1/s1
|
| Chemical Name |
(5S)-3-(2,5-difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-5-(hydroxymethyl)-N-methyl-5-phenyl-2H-pyrrole-1-carboxamide
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| Synonyms |
MK0731; MK 0731; MK-0731
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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 Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1763 mL | 10.8814 mL | 21.7628 mL | |
| 5 mM | 0.4353 mL | 2.1763 mL | 4.3526 mL | |
| 10 mM | 0.2176 mL | 1.0881 mL | 2.1763 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 |
| NCT00104364 | Completed | Drug: MK0731 | Cancer | Merck Sharp & Dohme LLC | May 2005 | Phase 1 |
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