体外活性：MELK-8a 是一种新型、有效的 MELK 抑制剂。 MELK 激酶在肿瘤发生中发挥重要作用。 MELK 参与细胞周期的调节，其基因缺失会导致高 MELK 表达的基底样乳腺癌细胞系子集的生长抑制。 MELK 抑制剂 8a 重现了细胞模型中短发夹核糖核酸 (shRNA) 介导的 MELK 敲低所观察到的细胞效应。研究发现，一种新型的氟诱导的疏水性塌陷将配体锁定在其生物活性构象中，并导致效力提高了 20 倍。这些新型药理学抑制剂在体内实现了高暴露并且耐受性良好，这可能允许进一步的体内评估。激酶测定：MELK-8a 盐酸盐是一种新型母体胚胎亮氨酸拉链激酶 (MELK) 抑制剂，IC50 为 2 nM。细胞测定：MELK 参与细胞周期的调节，其基因缺失会导致高 MELK 表达的基底样乳腺癌细胞系子集的生长抑制。将 MDA-MB-468 和 MCF7 细胞分别以 1000 和 4000 个细胞/孔的生长培养基接种到 96 孔板中。铺板后 16 小时，添加 MELK-8a 并孵育 7 天。对于每个孔，添加ATPLite试剂并孵育。在多标签读板机上测量发光

在 C57BL/6 小鼠中皮下注射 30 mg/kg 的 MELK-8a 可产生良好的血浆暴露。化合物快速吸收到体循环中（Tmax=0.4 h），血浆峰浓度达到 6.6 μM。雌性无胸腺裸鼠的剂量递增 PK 研究表明，化合物释放速率在 120 mg/kg 时达到最大，所有清除机制在 240 mg/kg 时可达到饱和。然而，当 C57BL/6 雄性小鼠以 10 mg/kg 口服给药时，其表现出非常差的 PK（口服生物利用度为 3.6%），而体内清除率非常高。

MELK-8a 盐酸盐是一种新型母体胚胎亮氨酸拉链激酶 (MELK) 抑制剂，IC50 为 2 nM。

MELK 参与细胞周期的调节，其基因缺失会导致高 MELK 表达的基底样乳腺癌细胞系子集的生长抑制。将 MDA-MB-468 和 MCF7 细胞分别以 1000 和 4000 个细胞/孔的生长培养基接种到 96 孔板中。铺板后 16 小时，添加 MELK-8a 并孵育 7 天。对于每个孔，添加ATPLite试剂并孵育。在多标记读板器上测量发光。

[1]. Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight. J Med Chem. 2016 May 26;59(10):4711-23.

C25H32N6O

432.56

1922153-17-0

MELK-8a hydrochloride;2096992-20-8

CN1CCN(CC1)C2=CC=C(C=C2)N3C=C(C=N3)C4=C(C=NC=C4)OCC5CCNCC5

BLFBSGVUERKSST-UHFFFAOYSA-N

InChI=1S/C25H32N6O/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

1-methyl-4-[4-[4-[3-(piperidin-4-ylmethoxy)pyridin-4-yl]pyrazol-1-yl]phenyl]piperazine

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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.

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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).

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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)

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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).

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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

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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.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。