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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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Purity: ≥98%
MELK-8a HCl is a novel, highly potent and selective MELK (Maternal Embryonic Leucine Zipper Kinase) inhibitor. MELK kinase has been suggested to be a key player in the development of tumors. A subset of basal-like breast cancer cell lines with high MELK expression experience growth inhibition as a result of genetic MELK depletion. MELK is involved in the regulation of cell cycle. Short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models is recapitulated by MELK inhibitors 8a. It was discovered that a novel hydrophobic collapse caused by fluorine locked the ligand in its bioactive conformation and produced a 20-fold increase in potency. These brand-new pharmacological inhibitors had a good safety profile and high levels of in vivo exposure, which may open the door for more in vivo testing.
| Targets |
MELK (IC50 = 2 nM)
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| ln Vitro |
MELK-8a remains very potent (IC50=140 nM) when the ATP concentration in the biochemical assay is shifted from 20 μM to 2 mM. The difference in potency between the catalytic domain construct and full-length MELK (5 nM versus 2 nM) is clearly visible. In addition to MELK, it only inhibits seven other off-target kinases, showing excellent selectivity with >85% binding inhibition at 1 μM .
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| ln Vivo |
In C57BL/6 mice, plasma exposure from the subcutaneous administration of MELK-8a at 30 mg/kg is good. Peak plasma concentration reaches 6.6 M and compound adsorption into the systemic circulation occurs quickly (Tmax=0.4 h). According to an ascending dose PK study done on female athymic nude mice, all clearance mechanisms can be saturated at 240 mg/kg, where the rate of compound release is at its maximum. On the other hand, it exhibits very poor PK (3.6% oral bioavailability) in C57BL/6 male mouse models when given orally at a dose of 10 mg/kg[1].
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| Cell Assay |
MDA-MB-468 and MCF7 cells are seeded at 1000 and 4000 cells/well in 96-well plates of growth medium, respectively. MELK-8a is added 16 hours after plating and is incubated for 7 days. The ATPLite reagent is added to each well and then incubated. A multi-label plate reader is used to measure luminescence[1].
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| Animal Protocol |
Mice: The intravenous and oral doses are prepared in a solution containing 5% ethanol, 100% PG, 5% CremophorEL, and 80% PBS for pharmacokinetic studies. The formulation for the subcutaneous dose is 10% PG and 25% (20%, v/v) Solutol. Prior to MELK-8a analysis, plasma samples are collected at predetermined intervals and kept frozen (20 °C). MELK-8a drug levels in plasma are quantified using an LC-MS/MS technique[1].
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| References |
| Molecular Formula |
C25H32N6O-HCL
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| Molecular Weight |
469.02
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| Elemental Analysis |
C, 64.02; H, 7.09; Cl, 7.56; N, 17.92; O, 3.41
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| CAS # |
2096992-20-8
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| Related CAS # |
MELK-8a;1922153-17-0
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| Appearance |
Solid powder
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| SMILES |
CN1CCN(CC1)C2=CC=C(C=C2)N3C=C(C=N3)C4=C(C=NC=C4)OCC5CCNCC5.Cl
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| InChi Key |
AFGMSRRNYDSRPT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H32N6O.ClH/c1-29-12-14-30(15-13-29)22-2-4-23(5-3-22)31-18-21(16-28-31)24-8-11-27-17-25(24)32-19-20-6-9-26-10-7-20;/h2-5,8,11,16-18,20,26H,6-7,9-10,12-15,19H2,1H3;1H
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| Chemical Name |
1-methyl-4-[4-[4-[3-(piperidin-4-ylmethoxy)pyridin-4-yl]pyrazol-1-yl]phenyl]piperazine;hydrochloride
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 50 mg/mL (106.61 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1321 mL | 10.6605 mL | 21.3211 mL | |
| 5 mM | 0.4264 mL | 2.1321 mL | 4.2642 mL | |
| 10 mM | 0.2132 mL | 1.0661 mL | 2.1321 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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