|1-((1H-吡唑-4-基)甲基)-4-甲基-5-((4-((6-(2,2,2-三氟乙基)噻吩并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)甲基)-1H-吲哚-2-甲腈|CsnPharm

CAS No.: 1857417-13-0

MI-503 Catalog No. CSN13934

MI-503 is a small molecule inhibitor of themenin-MLL interaction.

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纯度 & 质量文件批次:

靶点选择性

生物活性

实验方案

技术信息

生物活性

描述MI-503 is a potent inhibitor of menin-MLL interaction with IC50 value of 14.7nM. It disrupted menin-MLL interaction at 1μM and 3μM in HEK293 cells transfected with MLL-AF9. MI-503 selectively and potently inhibited MLL leukemia cells proliferation with GI50 values ranging in 0.25-0.57μM, effectively induced differentiation of MLL leukemia cells, increased cell apoptosis at 1μM and 2μM, and led to markedly reduced expression of Hoxa9 and Meis1, downstream targets of MLL fusion proteins substantially upregulated in MLL leukemias. Inhibition of menin-MLL through MI-503 reverse gene expression signatures associated with MLL-rearranged leukemia cells, such as homeobox genes (HOXA9, HOXA10, MEIS1, and PBX3), FLT3, and other downstream targets of MLL fusion proteins (MEF2C, BCL2, and CDK6). Administration of MI-503 at dose of 60mg/kg, i.p., blocked hematologic tumors in vivo and reduce MLL leukemia tumor burden. Oral gavage of MI-503 at 80 mg/kg improved survival of MLL leukemic mice^[2].
作用机制MI-503 occupies the F9 and P13 pockets on menin, forming a hydrogen bond with Tyr276, and also extends beyond the P13 pocket to form hydrogen bonds with Trp341 and Glu366.^[2]
动物研究
剂量
Mice: 35 mg/kg, 60 mg/kg^[1] (i.p.)

给药途径
i.p.
参考文献

动物研究
剂量	Mice: 35 mg/kg, 60 mg/kg^[1] (i.p.)
给药途径	i.p.

[1] Borkin D, He S, et al. Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo. Cancer Cell. 2015 Apr 13;27(4):589-602.
[2] Borkin D, He S, Miao H, Kempinska K, Pollock J, Chase J, Purohit T, Malik B, Zhao T, Wang J, Wen B, Zong H, Jones M, Danet-Desnoyers G, Guzman ML, Talpaz M, Bixby DL, Sun D, Hess JL, Muntean AG, Maillard I, Cierpicki T, Grembecka J. Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo. Cancer Cell. 2015 Apr 13;27(4):589-602. doi: 10.1016/j.ccell.2015.02.016. Epub 2015 Mar 26. PMID: 25817203; PMCID: PMC4415852.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 1.7711 mL
- 8.8554 mL
- 17.7108 mL
- 5 mM
- 0.3542 mL
- 1.7711 mL
- 3.5422 mL
- 10 mM
- 0.1771 mL
- 0.8855 mL
- 1.7711 mL

技术信息

CAS号

1857417-13-0

储存条件

粉末: Keep in dark place,Sealed in dry,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C28H27F3N8S

运输

蓝冰

分子量

564.63

别名

溶解度

DMSO	95.0 mg/mL (168.3 mM) warming
Water	Insoluble
Ethanol	3.0 mg/mL (5.3 mM) warming

动物实验配方

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