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.
Physicochemical Properties
| Molecular Formula | C25H28N3O2F3 |
| Molecular Weight | 459.50392 |
| Exact Mass | 459.213 |
| Elemental Analysis | C, 65.35; H, 6.14; F, 12.40; N, 9.14; O, 6.96 |
| CAS # | 845256-65-7 |
| Related CAS # | 845256-65-7 |
| PubChem CID | 11655511 |
| Appearance | Solid powder |
| Density | 1.3±0.1 g/cm3 |
| Boiling Point | 590.5±50.0 °C at 760 mmHg |
| Flash Point | 310.9±30.1 °C |
| Vapour Pressure | 0.0±1.7 mmHg at 25°C |
| Index of Refraction | 1.615 |
| LogP | 3.61 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 33 |
| Complexity | 732 |
| Defined Atom Stereocenter Count | 3 |
| 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 |
| 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 |
| Synonyms | MK0731; MK 0731; MK-0731 |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| Targets | KSP (IC50 = 2.2 nM) |
| 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. |
| 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 |
| 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]. 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]. 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. |
| Additional Infomation |
MK-0731 is a kinesin spindle protein inhibitor and antineoplastic agent. MK0731 is a synthetic small molecule with potential antineoplastic activity. MK0731 selectively inhibits kinesin spindle protein (KSP), which may result in the inhibition of mitotic spindle assembly, induction of cell cycle arrest during the mitotic phase, and apoptosis in tumor cells that overexpress KSP. |
Solubility Data
| Solubility (In Vitro) | May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples |
| 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 (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *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). 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)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL 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). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |