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]。