Monastrol
(Synonyms: (±)-Monastrol) 目录号 : GC14929
Monastrol是一种强效且具细胞通透性的有丝分裂驱动蛋白Eg5抑制剂，其 IC50为14μM。
Cas No.:254753-54-3;329689-23-8
Sample solution is provided at 25 µL, 10mM.
Monastrol is a potent and cell-permeable inhibitor of the mitotic kinesin Eg5 with an IC50 value of 14μM[1]. Eg5 is a homotetrameric motor protein of the kinesin-5 family that uses ATP hydrolysis to slide along microtubules, playing a central role in spindle-pole separation and maintaining the bipolarity of the mitotic spindle[2]. Monastrol, by binding the allosteric pocket of Eg5, blocks ADP release and suppresses the motor’s microtubule-based motility, serving as a widely employed tool for dissecting cell division, spindle dynamics, and anti-cancer mechanisms[3][4].
In vitro, Monastrol (5–100μM; 24–48h) selectively suppressed MCF-7 breast-cancer cell proliferation, reduced cell viability, lowered the normalized cell index by 30–40%, arrested cells in G1 and G2/M, raised the mitotic index and up-regulated p21/CDKN1A mRNA, all without inducing apoptosis[5]. Monastrol (100µM; 48h) significantly inhibited the invasion ability of HCT-116 and DLD-1 colorectal cancer cells with high fascin expression[6].
In vivo, Monastrol (1mg/kg; i.p.; twice weekly for 4 weeks; given 10min before each bortezomib dose) reversed bortezomib-induced sensory neuropathy in C57BL/6 mice, shortening tail sensory latency by 25% and cold-withdrawal time by 40%, fully preserving intra-epidermal nerve fiber density, and restoring sciatic/tibial unmyelinated fiber caliber while attenuating axonal atrophy[7].
References:
[1] Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science. 1999;286(5441):971-974.
[2] Mann BJ, Wadsworth P. Kinesin-5 Regulation and Function in Mitosis. Trends Cell Biol. 2019;29(1):66-79.
[3] Maliga Z, Mitchison TJ. Small-molecule and mutational analysis of allosteric Eg5 inhibition by monastrol. BMC Chem Biol. 2006;6:2.
[4] Garcia-Saez I, Skoufias DA. Eg5 targeting agents: From new anti-mitotic based inhibitor discovery to cancer therapy and resistance. Biochem Pharmacol. 2021;184:114364.
[5] Marques LA, Semprebon SC, Niwa AM, et al. Antiproliferative activity of monastrol in human adenocarcinoma (MCF-7) and non-tumor (HB4a) breast cells. Naunyn Schmiedebergs Arch Pharmacol. 2016;389(12):1279-1288.
[6] Alburquerque-González B, Montoro-García S, Bernabé-García Á, et al. Monastrol suppresses invasion and metastasis in human colorectal cancer cells by targeting fascin independent of kinesin-Eg5 pathway. Biomed Pharmacother. 2024;175:116785.
[7] Bobylev I, Peters D, Vyas M, et al. Kinesin-5 Blocker Monastrol Protects Against Bortezomib-Induced Peripheral Neurotoxicity. Neurotox Res. 2017;32(4):555-562.
Monastrol是一种强效且具细胞通透性的有丝分裂驱动蛋白Eg5抑制剂，其 IC50为14μM[1]。Eg5是驱动蛋白-5家族的四聚体马达蛋白，通过ATP水解沿微管滑动，在纺锤体两极分离和维持有丝分裂纺锤体双极性中发挥核心作用[2]。Monastrol 通过结合Eg5的变构位点阻断ADP释放，抑制Eg5在纺锤体微管上的运动活性，常用于细胞分裂、纺锤体动力学及抗癌机制研究[3][4]。
体外实验中，Monastrol（5–100μM；24–48h）选择性抑制MCF-7乳腺癌细胞增殖，降低细胞活力，使归一化细胞指数下降30–40%，将细胞阻滞于G1和G2/M期，显著提高有丝分裂指数并上调p21/CDKN1A mRNA，但未诱导凋亡[5]。Monastrol（100μM；48h）显著抑制高表达fascin的HCT-116和DLD-1结直肠癌细胞的侵袭能力[6]。
体内实验中，Monastrol（1mg/kg；腹腔注射；每周2次；持续4周；每次在硼替佐米给药前10min给予）逆转了C57BL/6小鼠因硼替佐米诱导的感觉神经病，使尾部感觉神经潜伏期缩短25%，冷刺激抬爪时间缩短40%，完全保留了表皮内神经纤维密度，并恢复坐骨神经/胫神经无髓纤维的平均直径，从而减轻轴突萎缩[7]。
| Cell experiment [1]: | |
Cell lines | human breast adenocarcinoma MCF-7 cells |
Preparation Method | The human breast adenocarcinoma MCF-7 cells were grown in DMEM supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin at 37°C and 5% CO2. Monastrol was dissolved in dimethyl sulfoxide (DMSO) and diluted in Dulbecco’s modified Eagle’s medium, where the concentration of DMSO did not exceed 0.5% in culture. The cytotoxicity assay was performed with MTT assay. Cells were seeded in 96-well culture plates (5×103 cells/well) and incubated for 24h for stabilization. After this period, the following treatments were administered for 24 and 48h: vehicle control (0.5% DMSO) and Monastrol at 5, 25, 50, 75, and 100μM. After each time of treatment, the medium was withdrawn, serum-free media containing 0.5mg/mL MTT salt was added and incubated for 4h, and formazan crystal products were diluted. The absorbance at 540nm was converted to a percentage of surviving cells. The assay was performed in triplicate in three independent experiments. The xCELLigence–real-time cell analyzer (RTCA) system was used to monitor the dynamics of cell proliferation using the electric impedance. |
Reaction Conditions | 5–100μM; 24–48h |
Applications | Monastrol selectively suppressed MCF-7 breast-cancer cell proliferation, reduced cell viability. |
| Animal experiment [2]: | |
Animal models | C57BL/6J mice |
Preparation Method | Adult wild-type C57BL/6J mice were housed under standard conditions with regulated temperature (21 ± 1°C), under reversed 12/12h (light/dark) cycle, with food and water ad libitum. Bortezomib was dissolved in 100% dehydrated ethanol (1.2mg/ml) and diluted 1:1 with 0.9% saline. Monastrol was dissolved in DMSO (10mg/ml) and diluted 1:10 with 0.9% saline. Mice (N = 5 per group) were treated with either 0.6mg/kg BZ intravenously (i.v.) or with a combination of 1mg/kg Monastrol intraperitoneally (i.p.), 10min prior to 0.6mg/kg BZ treatment. The control group (CTRL) was treated with vehicle i.v. (100% dehydrated ethanol and 0.9% saline, diluted 1:1). All groups were treated twice per week for 4 weeks. For the measurement of the sensory nerve conduction, the needle electrodes were placed on the tail. The measurements were performed 20min before the first administration of the drugs (day 0) and 24h after the last administration (day 28). |
Dosage form | 1mg/kg; i.p.; twice weekly for 4 weeks; given 10min before each bortezomib dose |
Applications | Monastrol reversed bortezomib-induced sensory neuropathy in C57BL/6 mice, shortening tail sensory latency by 25%. |
References: | |
| Cas No. | 254753-54-3;329689-23-8 | SDF | |
| 别名 | (±)-Monastrol | ||
| 化学名 | ethyl 6-(3-hydroxyphenyl)-2-mercapto-4-methyl-1,6-dihydropyrimidine-5-carboxylate | ||
| Canonical SMILES | CCOC(C(C1C2=CC(O)=CC=C2)=C(N=C(S)N1)C)=O | ||
| 分子式 | C14H16N2O3S | 分子量 | 292.35 |
| 溶解度 | ≥ 29.2mg/mL in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.4206 mL | 17.1028 mL | 34.2056 mL |
| 5 mM | 0.6841 mL | 3.4206 mL | 6.8411 mL |
| 10 mM | 0.3421 mL | 1.7103 mL | 3.4206 mL |
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