MI-538
目录号 : GC32798
MI-538是menin和MLL融合蛋白相互作用的抑制剂；IC50值为21nM。
Cas No.:1857417-10-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | MOLM-13, MV4;11, HL-60 human leukemia cells as well as MLL-AF9 and HM-2 murine bone marrow cells are treated with MI-538 or 0.25% DMSO for 7 days. Media are changed at day 4 with viable cell number restored to the original concentration, and MI-538 are resupplied. An amount of 100 μL of cell suspension is transferred to 96-well plates for each sample in quadruplicates. Cell viability is measured using the MTT assay. Plates are read for absorbance at 570 nm[1]. |
Animal experiment: | Mice: Mice xenograft are randomly grouped with each group containing eight mice. Vehicle or MI-538 (45 mg/kg) are administrated once daily at designated doses using ip injections for 2 weeks. Body weight and tumor sizes are monitored three times a week[1]. |
References: [1]. Borkin D, et al. Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein-Protein Interaction between Menin and Mixed Lineage Leukemia (MLL). J Med Chem. 2016 Feb 11;59(3):892-913. | |
MI-538 is an inhibitor of the interaction between menin and MLL fusion proteins with an IC50 of 21 nM.
MI-538 inhibits the proliferation of MLL leukemia cells with a GI50 of 83 nM. MI-538 shows no effect (up to 6 μM) on growth of the control cell lines HL-60 and HM-2, which do not harbor MLL translocations, demonstrating good selectivity toward MLL fusion protein transformed cells. MI-538 binds to menin with low nanomolar affinity (Kd=6.5 nM). Its potent cellular activity originates from the improved binding affinity to menin and possibly increased cell membrane permeability. Treatment with MI-538 results in strong down regulation of expression of Hoxa9 and Meis1 genes. About 100 nM 27 was sufficient to reduce by ~50% Hoxa9 expression in MLL-AF9 cells, and even more pronounced effect was seen on Meis1 expression[1].
Treatment with MI-538 results in a pronounced, about 80%, reduction in the MV4;11 tumor volume, without causing substantial signs of toxicity reflected by less than 10% reduction of the body weight. MI-538 demonstrates markedly improved exposure (area under the curve, AUC, values), Cmax (maximum compound concentration) in the blood plasma, and the lowest value of clearance. The half-life of MI-538 is about 1.6 h. MI-538 has also high oral bioavailability (~50%)[1].
[1]. Borkin D, et al. Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein-Protein Interaction between Menin and Mixed Lineage Leukemia (MLL). J Med Chem. 2016 Feb 11;59(3):892-913.
| Cas No. | 1857417-10-7 | SDF | |
| Canonical SMILES | FC(F)(F)CC(S1)=CC2=C1N=CN=C2NC3CCN(CC4=C(O)C=C(N(CC5=CNN=C5)C(C#N)=C6)C6=C4)CC3 | ||
| 分子式 | C27H25F3N8OS | 分子量 | 566.6 |
| 溶解度 | DMSO : 100 mg/mL (176.49 mM);Water : < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.7649 mL | 8.8246 mL | 17.6491 mL |
| 5 mM | 0.353 mL | 1.7649 mL | 3.5298 mL |
| 10 mM | 0.1765 mL | 0.8825 mL | 1.7649 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein-Protein Interaction between Menin and Mixed Lineage Leukemia (MLL)
J Med Chem 2016 Feb 11;59(3):892-913.PMID:26744767DOI:10.1021/acs.jmedchem.5b01305.
Development of potent small molecule inhibitors of protein-protein interactions with optimized druglike properties represents a challenging task in lead optimization process. Here, we report synthesis and structure-based optimization of new thienopyrimidine class of compounds, which block the protein-protein interaction between menin and MLL fusion proteins that plays an important role in acute leukemias with MLL translocations. We performed simultaneous optimization of both activity and druglike properties through systematic exploration of substituents introduced to the indole ring of lead compound 1 (MI-136) to identify compounds suitable for in vivo studies in mice. This work resulted in the identification of compound 27 (MI-538), which showed significantly increased activity, selectivity, polarity, and pharmacokinetic profile over 1 and demonstrated a pronounced effect in a mouse model of MLL leukemia. This study, which reports detailed structure-activity and structure-property relationships for the menin-MLL inhibitors, demonstrates challenges in optimizing inhibitors of protein-protein interactions for potential therapeutic applications.