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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)
|
|---|---|
| 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 |
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| Additional Infomation |
MK-0731 is a kinesin spindle protein inhibitor and an antitumor drug. MK0731 is a synthetic small molecule with potential antitumor activity. MK0731 selectively inhibits kinesin spindle protein (KSP), which may lead to inhibition of spindle assembly during mitosis, induce cell cycle arrest during mitosis, and cause apoptosis in KSP-overexpressing tumor cells.
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| Molecular Formula |
C25H28N3O2F3
|
|---|---|
| Molecular Weight |
459.50392
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| 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
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| Related CAS # |
845256-65-7
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| PubChem CID |
11655511
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| 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
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| 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
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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 Vitro) |
DMSO: ~50 mg/mL (~108.8 mM; with ultrasonication)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: formulated as a solution in acidified saline at pH 4.0, 100 μL (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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