MK-5108 (VX-689) is a potent ATP-competitive inhibitor of Aurora A kinase with an IC50 value of 0.064nM [1]. MK-5108 induces G2/M accumulation and polyploidy in cells, and diminishes the expression of Aurora A kinase as well as the downstream of TACC3 and Plk1 [2]. MK-5108 has been widely used to inhibit the growth arrest and death of various cancer cells [3].
In vitro, MK-5108 treatment for 72 hours significantly inhibits the proliferation of H460 cells and A427 cells, with IC50 values of 0.25μM and 0.13μM, respectively[4]. Treatment with MK-5108 (0.4μM) in combination with trametinib (8nM) for 24 hours significantly induced cell cycle arrest in HCT116 cells and inhibited the expression of proteins related to the G1/S phase progression[5]. Treatment with MK-5108 (0.1μM) for 48 hours can induce autophagy in IMR-32 cells, as evidenced by the increased expression level of LC3A/B-II protein[6].
In vivo, MK-5108 treatment via intraperitoneal injection at a dose of 20mg/kg/day for 5 consecutive days significantly reduced renal fibrosis and collagen deposition in the unilateral ureteral obstruction (UUO) mouse model, and alleviated renal inflammation[7]. Administering MK-5108 (30mg/kg) orally twice daily for 12 consecutive days significantly inhibited the growth of xenograft tumors in SCID mice bearing HCT116 tumors[8].
References:
[1] Amin M, Minton S E, LoRusso P M, et al. A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors[J]. Investigational new drugs, 2016, 34(1): 84-95.
[2] Chinn D C, Holland W S, Mack P C. Anticancer activity of the Aurora A kinase inhibitor MK-5108 in non-small-cell lung cancer (NSCLC) in vitro as monotherapy and in combination with chemotherapies[J]. Journal of cancer research and clinical oncology, 2014, 140(7): 1137-1149.
[3] Kretzner L, Scuto A, Claudia K, et al. Combination Therapy with the Histone Deacetylase Inhibitor Vorinostat Plus the Novel Aurora Kinase A Inhibitor MK-5108 Leads to Enhanced Lymphoma Cell Death Due to Acetylation of p53 and Repression of c-Myc, hTERT, and miRNA Levels[J]. Blood, 2009, 114(22): 1690.
[4] Chinn D C, Holland W S, Mack P C. Anticancer activity of the Aurora A kinase inhibitor MK-5108 in non-small-cell lung cancer (NSCLC) in vitro as monotherapy and in combination with chemotherapies[J]. Journal of cancer research and clinical oncology, 2014, 140(7): 1137-1149.
[5] Sato M, Yamamoto Y, Moriwaki T, et al. Combination of AURKA inhibitor and MEK inhibitor strongly enhances G1 arrest and induces synergistic antitumor effect on KRAS or BRAF mutant colon cancer cells[J]. Biochemistry and Biophysics Reports, 2025, 43: 102073.
[6] Durbas M, Pabisz P, Wawak K, et al. GD2 ganglioside-binding antibody 14G2a and specific aurora A kinase inhibitor MK-5108 induce autophagy in IMR-32 neuroblastoma cells[J]. Apoptosis, 2018, 23(9): 492-511.
[7] Jiang M, Bai M, Xu S, et al. Blocking AURKA with MK-5108 attenuates renal fibrosis in chronic kidney disease[J]. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2021, 1867(11): 166227.
[8] Shimomura T, Hasako S, Nakatsuru Y, et al. MK-5108, a highly selective Aurora-A kinase inhibitor, shows antitumor activity alone and in combination with docetaxel[J]. Molecular cancer therapeutics, 2010, 9(1): 157-166.
MK-5108 (VX-689)是一种有效的ATP竞争性Aurora A激酶抑制剂，IC50值为0.064nM[1]。MK-5108诱导细胞发生G2/M期积累和多倍体化，并减少Aurora A激酶及下游TACC3和Plk1的表达[2]。MK-5108已被广泛用于抑制多种癌细胞的生长停滞和死亡[3]。
在体外，MK-5108处理72小时显著抑制了H460细胞和A427细胞的增殖，IC50值分别为0.25μM和0.13μM[4]。MK-5108 (0.4μM) 联合trametinib (8nM) 处理HCT116细胞24小时，显著诱导了细胞周期阻滞，并抑制了与G1/S期进程相关的蛋白表达[5]。用MK-5108 (0.1μM) 处理IMR-32细胞48小时，可诱导细胞自噬，表现为LC3A/B-II蛋白表达水平升高[4]。
在体内，每日腹腔注射20mg/kg剂量的MK-5108，连续5天，显著减少了单侧输尿管梗阻（UUO）小鼠模型中的肾纤维化和胶原沉积，并减轻了肾脏炎症[7]。每日两次口服30mg/kg剂量的MK-5108，连续12天，显著抑制了携带HCT116肿瘤的SCID小鼠体内异种移植瘤的生长[8]。