AZD6244(Selumetinib) is an oral, small molecule, specific ATP non-competitive inhibitor of MEK1/2 proteins, with the IC50 of 14.1 ± 0.79nM [1]. AZD6244 binds to a unique specific allosteric pocket on the N-terminal domain of MEK1/2 adjacent to the canonical ATP binding site, which results in a conformational change that prevents RaF-induced phosphorylation and locks MEK1/2 in a catalytically inactive state, preventing ERK1/2 activation and inhibiting MAPK signaling[2]. AZD6244 has been widely used in various cellular and animal models for anti-cancer studies[3].
In vitro, AZD6244 treatment for 72 hours significantly inhibited the proliferation of RMG-I and SMOV-2 cells, with an IC50 of 78nM and 850nM, respectively[4]. Treatment of SGC7901 cells with 4000nM AZD6244 for 48 hours significantly inhibited cell proliferation and cell viability, promoted apoptosis, and resulted in a decrease in p-ERK levels[5]. Treatment of Epstein-Barr virus (EBV)-infected HONE-1 cells with AZD6244 at a concentration of 5000nM for 24h inhibited cell proliferation, resulting in cell cycle arrest and an increase in the proportion of apoptotic cells[6].
In vivo, AZD6244 treatment via oral administration at a dose of 50mg/kg twice daily for 21 days significantly inhibited tumor volume growth without altering body weight in a xenograft model bearing hepatocellular carcinoma[7]. Oral administration of AZD6244 at a dose of 30mg/kg daily prevented weight loss, reduced tumor burden, and attenuated muscle atrophy in the mouse cachexia models[8].
References:
[1] Campagne O, Yeo K K, Fangusaro J, et al. Clinical pharmacokinetics and pharmacodynamics of selumetinib[J]. Clinical pharmacokinetics, 2021, 60(3): 283-303.
[2] Roskoski Jr R. Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the treatment of cutaneous melanomas[J]. Pharmacological Research, 2017, 117: 20-31.
[3] Ciombor K K, Bekaii-Saab T. Selumetinib for the treatment of cancer[J]. Expert opinion on investigational drugs, 2015, 24(1): 111-123.
[4] Bartholomeusz C, Oishi T, Saso H, et al. MEK1/2 Inhibitor Selumetinib (AZD6244) inhibits growth of ovarian clear Cell Carcinoma in a PEA-15–dependent manner in a mouse Xenograft Model[J]. Molecular cancer therapeutics, 2012, 11(2): 360-369.
[5] Gao J H, Wang C H, Tong H, et al. Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer[J]. Scientific Reports, 2015, 5(1): 16382.
[6] Ma B B Y, Lui V W Y, Cheung C S, et al. Activity of the MEK inhibitor selumetinib (AZD6244; ARRY-142886) in nasopharyngeal cancer cell lines[J]. Investigational new drugs, 2013, 31(1): 30-38.
[7] Huynh H, Soo K C, Chow P K H, et al. Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma[J]. Molecular cancer therapeutics, 2007, 6(1): 138-146.
[8] Quan-Jun Y, Yan H, Yong-Long H, et al. Selumetinib attenuates skeletal muscle wasting in murine cachexia model through ERK inhibition and AKT activation[J]. Molecular cancer therapeutics, 2017, 16(2): 334-343.
AZD6244(Selumetinib)是一种口服小分子特异性MEK1/2蛋白ATP非竞争性抑制剂，IC50值为14.1± 0.79nM[1]。AZD6244通过与MEK1/2氨基末端结构域中毗邻经典ATP结合位点的独特变构口袋结合，诱导构象变化从而阻止Raf介导的磷酸化，将MEK1/2锁定在催化失活状态，进而抑制ERK1/2激活及MAPK信号通路[2]。AZD6244已广泛应用于多种癌症研究的细胞和动物模型[3]。
在体外，AZD6244处理72小时可显著抑制RMG-I和SMOV-2细胞增殖，IC50值分别为78nM和850nM[4]。4000nM的AZD6244处理SGC7901细胞48小时能显著抑制细胞增殖与活力、促进凋亡，并降低p-ERK水平[5]。5000nM的AZD6244处理EB病毒感染的HONE-1细胞24小时可抑制细胞增殖，导致细胞周期阻滞并增加凋亡细胞比例[6]。
在体内，肝细胞癌异种移植瘤小鼠模型经口服AZD6244（50mg/kg，每日两次，持续21天）后，肿瘤体积增长被显著抑制且小鼠体重无变化[7]。癌症恶病质小鼠模型每日口服30mg/kg 剂量的AZD6244可防止体重减轻、降低肿瘤负荷并缓解肌肉萎缩[8]。